Itraconazole compositions and dosage forms, and methods of using the same

ABSTRACT

The disclosure relates to, among other things, pharmaceutical compositions, such as solid oral dosage forms, comprising itraconazole, methods of making the compositions, and methods of using the same for treating disorders including, but not limited to, fungal infections.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/198,645, filed Nov. 21, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/623,742, filed Jun. 15, 2017, which is acontinuation of U.S. patent application Ser. No. 14/882,662, filed Oct.14, 2015, now U.S. Pat. No. 9,713,642, which is a continuation of U.S.patent application Ser. No. 14/511,420, filed Oct. 10, 2014, now U.S.Pat. No. 9,272,046, which is a continuation of U.S. patent applicationSer. No. 13/924,222, filed Jun. 21, 2013, now U.S. Pat. No. 8,921,374,which claims the benefit of priority to Australian Provisional PatentApplication No. 2012902624, filed on Jun. 21, 2012 and entitled“Itraconazole Formulations and Uses”, the contents of each of which arehereby incorporated by reference in its entirety for all purposes.

BACKGROUND

Itraconazole is a triazole antifungal compound that can be used for thetreatment of fungal infections, including superficial infections, suchas onychomycosis, as well as systemic fungal infections, for example,pulmonary or extrapulmonary blastomycosis, histoplasmosis, andaspergillosis. Solid oral dosage forms of itraconazole are commerciallyavailable under the tradename SPORANOX®. SPORANOX® must be taken withfood because bioavailability of the itraconazole in the SPORANOX®formulation is enhanced when ingested in the fasted state. Further, thebioavailability of itraconazole in SPORANOX® varies greatly both betweensubjects (inter-subject), and from dose to dose in a single subject(intra-subject).

This variability is particularly problematic because itraconazole isknown to have harmful side effects, especially upon overdosing. Knownside effects include gastrointestinal discomfort, dyspepsia, nausea,abdominal pain, constipation, vomiting, diarrhea, headache, increasedhepatic enzyme levels, menstrual disorders, dizziness, pruritus, rash,angioedema, and urticaria. Conversely, when insufficient itraconazole isadministered, efficacy of the itraconazole is minimal and can contributeto the evolution of multi-drug resistant microbes. Because of thevariability in bioavailability of SPORANOX® itraconazole, consistentdelivery of a therapeutically effective dose can be a challenge. Thus,improved itraconazole compositions, dosage forms, formulations, andmethods of using the same are needed.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides an oral pharmaceuticalcomposition comprising about 50 mg of itraconazole, wherein thecomposition exhibits an AUC0-t which is 80% to 125% of about 440 h*ng/mlto about 740 h*ng/ml following administration of the composition to asubject under fed conditions. In one embodiment, the compositionexhibits a Cmax which is 80% to 125% of about 60 ng/ml to about 75 ng/mlfollowing administration of the composition to a subject under fedconditions.

In one embodiment, the present composition under fed conditions istherapeutically similar to the reference composition under fedconditions. In another embodiment, the present composition exhibits anabsorption profile under fed conditions which is therapeutically similarto the absorption profile of the reference composition under fedconditions. In one embodiment, the present composition under fedconditions is bioequivalent to the reference composition under fedconditions. In another embodiment, the present composition exhibits anabsorption profile under fed conditions which is bioequivalent to theabsorption profile of the reference composition under fed conditions. Inone embodiment, the present composition under fasting conditions istherapeutically similar to the reference composition under fedconditions. In another embodiment, the present composition exhibits anabsorption profile under fasting conditions which is therapeuticallysimilar to the absorption profile of the reference composition under fedconditions. In one embodiment, the present composition under fastingconditions is bioequivalent to the reference composition under fedconditions. In another embodiment, the present composition exhibits anabsorption profile under fasting conditions which is bioequivalent tothe absorption profile of the reference composition under fedconditions. In one embodiment, the present composition under fedconditions is substantially similar to the same composition underfasting conditions. In another embodiment, the present compositionexhibits an absorption profile under fed conditions which issubstantially similar to the absorption profile of the same compositionunder fasting conditions.

In one embodiment, the present invention provides an oral pharmaceuticalcomposition comprising about 50 mg of itraconazole, wherein thecomposition exhibits an AUC_(0-t) which is 80% to 125% of about 350h*ng/ml to about 620 h*ng/ml following administration of the compositionto a subject under fasting conditions. In one embodiment, thecomposition exhibits a C_(max) which is 80% to 125% of about 30 ng/ml toabout 60 ng/ml following administration of the composition to a subjectunder fasting conditions.

In one embodiment, the present invention provides an oral pharmaceuticalcomposition comprising about 65 mg of itraconazole, wherein thecomposition exhibits an AUC_(0-t) which is 80% to 125% of about 650h*ng/ml to about 1200 h*ng/ml following administration of thecomposition to a subject under fed conditions. In one embodiment, thecomposition exhibits a C_(max) which is 80% to 125% of about 65 ng/ml toabout 100 ng/ml following administration of the composition to a subjectunder fed conditions.

In one embodiment, the present invention provides an oral pharmaceuticalcomposition comprising about 65 mg of itraconazole, wherein thecomposition exhibits an AUC_(0-t) which is 80% to 125% of about 450h*ng/ml to about 900 h*ng/ml following administration of the compositionto a subject under fasting conditions. In one embodiment, thecomposition exhibits a C_(max) which is 80% to 125% of about 36 ng/ml toabout 70 ng/ml following administration of the composition to a subjectunder fasting conditions.

In one embodiment, the present invention provides an oral pharmaceuticalcomposition comprising itraconazole, wherein the composition exhibits anAUC_(0-t) which is 80% to 125% of about 8.8 h*ng/ml to about 14.8h*ng/ml per milligram of itraconazole following administration of thecomposition to a subject under fed conditions.

In one embodiment, the present invention provides an oral pharmaceuticalcomposition comprising itraconazole, wherein the composition exhibits anAUC_(0-t) which is 80% to 125% of about 7.0 h*ng/ml to about 12.4h*ng/ml per milligram of itraconazole following administration of thecomposition to a subject under fasting conditions.

In one embodiment, the present composition exhibits a reducedvariability in the AUC_(0-t) as compared to the reference composition.In another embodiment, the present composition exhibits a variability inthe C_(max) and/or T_(max) as not worse than the reference composition.In another embodiment, the present composition exhibits a reducedvariability in the C_(max) and/or T_(max) as compared to the referencecomposition.

In one embodiment, the present invention provides an oral pharmaceuticalcomposition comprising itraconazole, which exhibits an intra-subjectcoefficient of variation under fed conditions for the AUC_(0-t) of lessthan about 35%. In one embodiment, the amount of itraconazole in thecomposition is about 50% to about 65% by weight of the amount ofitraconazole in a reference composition.

In one embodiment, the present invention provides an oral pharmaceuticalcomposition comprising itraconazole, which exhibits an inter-subjectcoefficient of variation under fed conditions for the AUC_(0-t) of lessthan about 35%. In one embodiment, the amount of itraconazole in thecomposition is about 50% to about 65% by weight of the amount ofitraconazole in a reference composition.

In one embodiment, the present invention provides oral pharmaceuticalcomposition comprising itraconazole, wherein the composition under fedconditions is substantially similar to the same composition underfasting conditions. In another embodiment, the present inventionprovides oral pharmaceutical composition comprising itraconazole,wherein the composition exhibits an absorption profile under fedconditions which is substantially similar to the absorption profile ofthe same composition under fasting conditions. In one embodiment, theamount of itraconazole in the composition is about 50% to about 65% byweight of the amount of itraconazole in a reference composition.

In one embodiment, the present invention provides a method of reducingfood effect of itraconazole in a subject comprising administering to thesubject an oral pharmaceutical composition comprising about 50 mg ofitraconazole, and the composition provides an AUC_(0-t) which is 80% to125% of about 440 h*ng/ml to about 740 h*ng/ml following administrationof the composition to a subject under fed conditions. In one embodiment,the composition exhibits an AUC_(0-t) which is 80% to 125% of about 350h*ng/ml to about 620 h*ng/ml following administration of the compositionto a subject under fasting conditions.

In one embodiment, the present invention provides a method of reducingfood effect of itraconazole in a subject comprising administering to thesubject an oral pharmaceutical composition comprising about 65 mg ofitraconazole, and the composition provides an AUC_(0-t) which is 80% to125% of about 650 h*ng/ml to about 1200 h*ng/ml following administrationof the composition to a subject under fed conditions. In one embodiment,the composition exhibits an AUC_(0-t) which is 80% to 125% of about 450h*ng/ml to about 900 h*ng/ml following administration of the compositionto a subject under fasting conditions.

In one embodiment, the present invention provides a method of reducingfood effect of itraconazole in a subject comprising administering to thesubject an oral pharmaceutical composition comprising of itraconazole,and the composition provides an AUC_(0-t) which is 80% to 125% of about8.8 h*ng/ml to about 14.8 h*ng/ml per milligram of itraconazolefollowing administration of the composition to a subject under fedconditions. In one embodiment, the composition provides an AUC_(0-t)which is 80% to 125% of about 7.0 h*ng/ml to about 12.4 h*ng/ml permilligram of itraconazole following administration of the composition toa subject under fasting conditions.

In one embodiment, the present invention provides a method of reducingintra-subject variability of itraconazole comprising administering to asubject an oral pharmaceutical composition comprising itraconazole, andthe composition exhibits an intra-subject coefficient of variation underfed conditions for the AUC_(0-t) of less than about 35%.

In one embodiment, the present invention provides a method of reducinginter-subject variability of itraconazole comprising administering tosubjects an oral pharmaceutical composition comprising itraconazole, andthe composition exhibits an inter-subject coefficient of variation underfed conditions for the AUC_(0-t) of less than about 35%.

In one embodiment, the present invention provides a method of treatingonychomycosis comprising administering to a subject an oralpharmaceutical composition comprising itraconazole, wherein the amountof itraconazole in the composition is about 50% to about 65% by weightof the amount of itraconazole in a reference composition and thecomposition is therapeutically equivalent to the reference composition.

In one embodiment, the present invention provides a method of treatingonychomycosis comprising administering to a subject an oralpharmaceutical composition comprising itraconazole, wherein the amountof itraconazole in the composition is about 50% to about 65% by weightof the amount of itraconazole in a reference composition and the methodprovides an effective cure with faster onset efficacy as compared to thereference composition. In one embodiment, the method exhibits efficacyend points at a time when the reference composition does not exhibitsefficacy end points. In one embodiment, the efficacy end points is atweek five, six, seven, eight, or nine.

In one embodiment, the present invention provides a method of treating adisease or condition comprising co-administering to a subject an oralpharmaceutical composition comprising itraconazole; and a gastric acidsuppressor or neutralizer.

In one embodiment, the present invention provides a method of treatingcancer comprising administering to a subject an oral pharmaceuticalcomposition of the present invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the linear scale graph of the plasma itraconazoleconcentration against time in a study assessing the relativebioavailability of various LOZANOC doses with a 100 mg dose SPORANOX®under fed conditions. Circles represent the reference SPORANOX® 100 mgdose; diamonds represent the 50 mg LOZANOC dose; stars represent the 60mg LOZANOC dose; and squares represent the 70 mg LOZANOC dose. All doseswere administered under fed conditions.

FIG. 2 shows the log-transformed scale graph of the plasma itraconazoleconcentration against time in a study assessing the relativebioavailability of various LOZANOC doses with a 100 mg dose SPORANOX®under fed conditions. Circles represent the reference SPORANOX® 100 mgdose; diamonds represent the 50 mg LOZANOC dose; stars represent the 60mg LOZANOC dose; and squares represent the 70 mg LOZANOC dose. All doseswere administered under fed conditions.

FIG. 3 shows the linear scale graph of the plasma hydroxyitraconazoleconcentration against time in a study assessing the relativebioavailability of various LOZANOC doses with a 100 mg dose SPORANOX®under fed conditions. Circles represent the reference SPORANOX® 100 mgdose; diamonds represent the 50 mg LOZANOC dose; stars represent the 60mg LOZANOC dose; and squares represent the 70 mg LOZANOC dose. All doseswere administered under fed conditions.

FIG. 4 shows the log-transformed scale graph of the plasmahydroxyitraconazole concentration against time in a study assessing therelative bioavailability of various LOZANOC doses with a 100 mg doseSPORANOX® under fed conditions. Circles represent the referenceSPORANOX® 100 mg dose; diamonds represent the 50 mg LOZANOC dose; starsrepresent the 60 mg LOZANOC dose; and squares represent the 70 mgLOZANOC dose. All doses were administered under fed conditions.

FIG. 5 shows the linear scale graph of the plasma itraconazoleconcentration against time in a study assessing the relativebioavailability of a 110 mg LOZANOC dose with a 200 mg dose of SPORANOX®(itraconazole) under fed and fasted conditions. Closed circles representthe reference SPORANOX® (itraconazole) 200 mg dose administered underfed conditions; open circles represent the reference SPORANOX®(itraconazole) 200 mg dose administered under fasted conditions; closedsquares represent the 110 mg LOZANOC dose administered under fedconditions; and open squares represent the 110 mg LOZANOC doseadministered under fasted conditions.

FIG. 6 shows the log-transformed scale graph of the plasma itraconazoleconcentration against time in a study assessing the relativebioavailability of a 110 mg LOZANOC dose with a 200 mg dose of SPORANOX®(itraconazole) under fed and fasted conditions. Closed circles representthe reference SPORANOX® (itraconazole) 200 mg dose administered underfed conditions; open circles represent the reference SPORANOX®(itraconazole) 200 mg dose administered under fasted conditions; closedsquares represent the 110 mg LOZANOC dose administered under fedconditions; and open squares represent the 110 mg LOZANOC doseadministered under fasted conditions.

FIG. 7 shows the linear scale graph of the plasma hydroxyitraconazoleconcentration against time in a study assessing the relativebioavailability of a 110 mg LOZANOC dose with a 200 mg dose of SPORANOX®(itraconazole) under fed and fasted conditions. Closed circles representthe reference SPORANOX® (itraconazole) 200 mg dose administered underfed conditions; open circles represent the reference SPORANOX®(itraconazole) 200 mg dose administered under fasted conditions; closedsquares represent the 110 mg LOZANOC dose administered under fedconditions; and open squares represent the 110 mg LOZANOC doseadministered under fasted conditions.

FIG. 8 shows the log-transformed scale graph of the plasmahydroxyitraconazole concentration against time in a study assessing therelative bioavailability of a 110 mg LOZANOC dose with a 200 mg dose ofSPORANOX® (itraconazole) under fed and fasted conditions. Closed circlesrepresent the reference SPORANOX® (itraconazole) 200 mg doseadministered under fed conditions; open circles represent the referenceSPORANOX® (itraconazole) 200 mg dose administered under fastedconditions; closed squares represent the 110 mg LOZANOC doseadministered under fed conditions; and open squares represent the 110 mgLOZANOC dose administered under fasted conditions.

FIG. 9 shows the regression analysis for the concentration of a 100 mgLOZANOC itraconazole dose administered under fed conditions once dailyfor 15 consecutive days.

FIG. 10 shows the regression analysis for the concentration of a 200 mgSPORANOX® itraconazole dose administered under fed conditions once dailyfor 15 consecutive days.

FIG. 11 shows a linear scale graph of the mean plasma itraconazoleconcentration over time in a study comparing the relativebioavailability of 100 mg LOZANOC dose administered under fed conditionswith 200 mg SPORANOX® administered under fed conditions once daily for15 consecutive days. Closed circles represent the 100 mg LOZANOCitraconazole dose administered under fed conditions; open circlesrepresent the reference SPORANOX® 200 mg dose administered under fedconditions once daily for 15 consecutive days.

FIG. 12 shows a log-scale graph of the mean plasma itraconazoleconcentration over time in a study comparing the relativebioavailability of 100 mg LOZANOC dose administered under fed conditionswith 200 mg SPORANOX® administered under fed conditions once daily for15 consecutive days. Closed circles represent the 100 mg LOZANOCitraconazole dose administered under fed conditions; open circlesrepresent the reference SPORANOX® 200 mg dose administered under fedconditions once daily for 15 consecutive days.

FIG. 13 shows the regression analysis for the concentration ofhydroxyitraconazole after administration of a 100 mg LOZANOCitraconazole dose under fed conditions once daily for 15 consecutivedays.

FIG. 14 shows the regression analysis for the concentration ofhydroxyitraconazole after administration of a 200 mg SPORANOX®itraconazole dose under fed conditions once daily for 15 consecutivedays.

FIG. 15 shows a linear scale graph of the mean plasmahydroxyitraconazole concentration over time in a study comparing therelative bioavailability of 100 mg LOZANOC dose with 200 mg SPORANOX®administered under fed conditions once daily for 15 consecutive days.Closed circles represent the 100 mg LOZANOC itraconazole doseadministered under fed conditions once daily for 15 consecutive days;open circles represent the reference SPORANOX® 200 mg dose administeredunder fed conditions once daily for 15 consecutive days.

FIG. 16 shows a log-scale graph of the mean plasma hydroxyitraconazoleconcentration over time in a study comparing the relativebioavailability of 100 mg LOZANOC dose with 200 mg SPORANOX®administered under fed conditions once daily for 15 consecutive days.Closed circles represent the 100 mg LOZANOC itraconazole doseadministered under fed conditions once daily for 15 consecutive days;open circles represent the reference SPORANOX® 200 mg dose administeredunder fed conditions once daily for 15 consecutive days.

FIG. 17 shows the regression analysis for the concentration of a 100 mgLOZANOC itraconazole dose administered under fed conditions twice dailyfor 14.5 consecutive days.

FIG. 18 shows the regression analysis for the concentration of a 200 mgSPORANOX® itraconazole dose administered under fed conditions twicedaily for 14.5 consecutive days.

FIG. 19 shows a linear scale graph of the mean plasma itraconazoleconcentration over time in a study comparing the relativebioavailability of 100 mg LOZANOC dose with 200 mg SPORANOX®administered under fed conditions twice daily for 14.5 consecutive days.Closed circles represent the 100 mg LOZANOC itraconazole doseadministered under fed conditions twice daily for 14.5 consecutive days;open circles represent the reference SPORANOX® 200 mg dose administeredunder fed conditions twice daily for 14.5 consecutive days.

FIG. 20 shows a log-scale graph of the mean plasma itraconazoleconcentration over time in a study comparing the relativebioavailability of 100 mg LOZANOC dose with 200 mg SPORANOX®administered under fed conditions twice daily for 14.5 consecutive days.Closed circles represent the 100 mg LOZANOC itraconazole doseadministered under fed conditions twice daily for 14.5 consecutive days;open circles represent the reference SPORANOX® 200 mg dose administeredunder fed conditions twice daily for 14.5 consecutive days.

FIG. 21 shows the regression analysis for the concentration ofhydroxyitraconazole after administration of a 100 mg LOZANOCitraconazole dose administered under fed conditions twice daily for 14.5consecutive days.

FIG. 22 shows the regression analysis for the concentration ofhydroxyitraconazole after administration of a 200 mg SPORANOX®itraconazole dose administered under fed conditions twice daily for 14.5consecutive days.

FIG. 23 shows a linear scale graph of the mean plasmahydroxyitraconazole concentration over time in a study comparing therelative bioavailability of 100 mg LOZANOC dose with 200 mg SPORANOX®administered under fed conditions twice daily for 14.5 consecutive days.Closed circles represent the 100 mg LOZANOC itraconazole doseadministered under fed conditions twice daily for 14.5 consecutive days;open circles represent the reference SPORANOX® 200 mg dose administeredunder fed conditions twice daily for 14.5 consecutive days.

FIG. 24 shows a log-scale graph of the mean plasma hydroxyitraconazoleconcentration over time in a study comparing the relativebioavailability of 100 mg LOZANOC dose with 200 mg SPORANOX®administered under fed conditions twice daily for 14.5 consecutive days.Closed circles represent the 100 mg LOZANOC itraconazole doseadministered under fed conditions twice daily for 14.5 consecutive days;open circles represent the reference SPORANOX® 200 mg dose administeredunder fed conditions twice daily for 14.5 consecutive days.

FIG. 25 shows a linear scale graph comparing the mean plasmaitraconazole concentration over time in a study assessing thebioavailability of a 50 mg or 100 mg LOZANOC dose with a 100 mg or 200mg dose of SPORANOX® administered under fasted conditions. Closedcircles represent the 50 mg LOZANOC dose administered under fastedconditions; open squares represent the 100 mg LOZANOC dose administeredunder fasted conditions; open circles represent the reference SPORANOX®100 mg dose administered under fasted conditions; open trianglesrepresent the reference SPORANOX® 200 mg dose administered under fastedconditions.

FIG. 26 shows a log-transformed graph comparing the mean plasmaitraconazole concentration over time in a study assessing thebioavailability of a 50 mg or 100 mg LOZANOC dose with a 100 mg or 200mg dose of SPORANOX® administered under fasted conditions. Closedcircles represent the 50 mg LOZANOC dose administered under fastedconditions; open squares represent the 100 mg LOZANOC dose administeredunder fasted conditions; open circles represent the reference SPORANOX®100 mg dose administered under fasted conditions; open trianglesrepresent the reference SPORANOX® 200 mg dose administered under fastedconditions.

FIG. 27 shows a linear scale graph comparing the mean plasmahydroxyitraconazole concentration over time in a study assessing thebioavailability of a 50 mg or 100 mg LOZANOC dose with a 100 mg or 200mg dose of SPORANOX® administered under fasted conditions. Closedcircles represent the 50 mg LOZANOC dose administered under fastedconditions; open squares represent the 100 mg LOZANOC dose administeredunder fasted conditions; open circles represent the reference SPORANOX®100 mg dose administered under fasted conditions; open trianglesrepresent the reference SPORANOX® 200 mg dose administered under fastedconditions.

FIG. 28 shows a log-transformed graph comparing the mean plasmahydroxyitraconazole concentration over time in a study assessing thebioavailability of a 50 mg or 100 mg LOZANOC dose with a 100 mg or 200mg dose of SPORANOX® administered under fasted conditions. Closedcircles represent the 50 mg LOZANOC dose administered under fastedconditions; open squares represent the 100 mg LOZANOC dose administeredunder fasted conditions; open circles represent the reference SPORANOX®100 mg dose administered under fasted conditions; open trianglesrepresent the reference SPORANOX® 200 mg dose administered under fastedconditions.

FIG. 29 shows a linear scale graph of the mean plasma itraconazoleconcentration over time in a study comparing the relativebioavailability of a 100 mg LOZANOC dose with a 100 mg dose of SPORANOX®administered under fed and fasted conditions. Closed circles representthe 50 mg LOZANOC dose administered under fasted conditions; opensquares represent the 50 mg LOZANOC dose administered under fedconditions; open circles represent the reference SPORANOX® 100 mg doseadministered under fasted conditions; open triangles represent thereference SPORANOX® 100 mg dose administered under fed conditions.

FIG. 30 shows a log-transformed scale graph of the mean plasmaitraconazole concentration over time in a study comparing the relativebioavailability of a 100 mg LOZANOC dose with a 100 mg dose of SPORANOX®administered under fed and fasted conditions. Closed circles representthe 50 mg LOZANOC dose administered under fasted conditions; opensquares represent the 50 mg LOZANOC dose administered under fedconditions; open circles represent the reference SPORANOX® 100 mg doseadministered under fasted conditions; open triangles represent thereference SPORANOX® 100 mg dose administered under fed conditions.

FIG. 31 shows a linear scale graph of the mean plasmahydroxyitraconazole concentration over time in a study comparing therelative bioavailability of a 100 mg LOZANOC dose with a 100 mg dose ofSPORANOX® administered under fed and fasted conditions. Closed circlesrepresent the 50 mg LOZANOC dose administered under fasted conditions;open squares represent the 50 mg LOZANOC dose administered under fedconditions; open circles represent the reference SPORANOX® 100 mg doseadministered under fasted conditions; open triangles represent thereference SPORANOX® 100 mg dose administered under fed conditions.

FIG. 32 shows a log-transformed scale graph of the mean plasmahydroxyitraconazole concentration over time in a study comparing therelative bioavailability of a 100 mg LOZANOC dose with a 100 mg dose ofSPORANOX® administered under fed and fasted conditions. Closed circlesrepresent the 50 mg LOZANOC dose administered under fasted conditions;open squares represent the 50 mg LOZANOC dose administered under fedconditions; open circles represent the reference SPORANOX® 100 mg doseadministered under fasted conditions; open triangles represent thereference SPORANOX® 100 mg dose administered under fed conditions.

FIG. 33 shows a linear graph of the mean plasma itraconazoleconcentration over time in a study assessing the relativebioavailability of a 50 mg LOZANOC dose with a 100 mg dose of SPORANOX®administered under fed and fasted conditions. Closed circles representthe 50 mg LOZANOC dose administered under fasted conditions; opencircles represent the 100 mg LOZANOC dose administered under fedconditions; closed squares represent the reference SPORANOX® 100 mg doseadministered under fasted conditions; and closed circles represent thereference SPORANOX® 100 mg dose administered under fed conditions.

FIG. 34 shows a log-transformed graph of the mean plasma itraconazoleconcentration over time in a study assessing the relativebioavailability of a 50 mg LOZANOC dose with a 100 mg dose of SPORANOX®administered under fed and fasted conditions. Closed circles representthe 50 mg LOZANOC dose administered under fasted conditions; opencircles represent the 100 mg LOZANOC dose administered under fedconditions; closed squares represent the reference SPORANOX® 100 mg doseadministered under fasted conditions; and closed circles represent thereference SPORANOX® 100 mg dose administered under fed conditions.

FIG. 35 shows a linear scale graph comparing the mean plasmaitraconazole concentration over time in a study assessing the relativebioavailability of a 50 mg LOZANOC dose with a 100 mg dose of SPORANOX®administered under fasted conditions. Closed circles represent the 50 mgLOZANOC dose administered under fasted conditions; open circlesrepresent the reference SPORANOX® 100 mg dose administered under fastedconditions.

FIG. 36 shows a log-transformed scale graph comparing the mean plasmaitraconazole concentration over time in a study assessing the relativebioavailability of a 50 mg LOZANOC dose with a 100 mg dose of SPORANOX®administered under fasted conditions. Closed circles represent the 50 mgLOZANOC dose administered under fasted conditions; open circlesrepresent the reference SPORANOX® 100 mg dose administered under fastedconditions.

FIG. 37 shows a linear scale graph comparing the mean plasmaitraconazole concentration over time in a study assessing the relativebioavailability of a 50 mg LOZANOC dose with a 100 mg dose of SPORANOX®administered under fed conditions. Closed circles represent the 50 mgLOZANOC dose administered under fed conditions; open circles representthe reference SPORANOX® 100 mg dose administered under fed conditions.

FIG. 38 shows a log-transformed scale graph comparing the mean plasmaitraconazole concentration over time in a study assessing the relativebioavailability of a 50 mg LOZANOC dose with a 100 mg dose of SPORANOX®administered under fed conditions. Closed circles represent the 50 mgLOZANOC dose administered under fed conditions; open circles representthe reference SPORANOX® 100 mg dose administered under fed conditions.

FIG. 39 shows a linear graph of the mean plasma hydroxyitraconazoleconcentration over time in a study assessing the relativebioavailability of a 50 mg LOZANOC dose with a 100 mg dose of SPORANOX®administered under fed and fasted conditions. Closed circles representthe 50 mg LOZANOC dose administered under fasted conditions; opencircles represent the 100 mg LOZANOC dose administered under fedconditions; closed squares represent the reference SPORANOX® 100 mg doseadministered under fasted conditions; and closed circles represent thereference SPORANOX® 100 mg dose administered under fed conditions.

FIG. 40 shows a log-transformed graph of the mean plasmahydroxyitraconazole concentration over time in a study assessing therelative bioavailability of a 50 mg LOZANOC dose with a 100 mg dose ofSPORANOX® administered under fed and fasted conditions. Closed circlesrepresent the 50 mg LOZANOC dose administered under fasted conditions;open circles represent the 100 mg LOZANOC dose administered under fedconditions; closed squares represent the reference SPORANOX® 100 mg doseadministered under fasted conditions; and closed circles represent thereference SPORANOX® 100 mg dose administered under fed conditions.

FIG. 41 shows a linear scale graph comparing the mean plasmahydroxyitraconazole concentration over time in a study assessing therelative bioavailability of a 50 mg LOZANOC dose with a 100 mg dose ofSPORANOX® administered under fasted conditions. Closed circles representthe 50 mg LOZANOC dose administered under fasted conditions; opencircles represent the reference SPORANOX® 100 mg dose administered underfasted conditions.

FIG. 42 shows a log-transformed scale graph comparing the mean plasmahydroxyitraconazole concentration over time in a study assessing therelative bioavailability of a 50 mg LOZANOC dose with a 100 mg dose ofSPORANOX® administered under fasted conditions. Closed circles representthe 50 mg LOZANOC dose administered under fasted conditions; opencircles represent the reference SPORANOX® 100 mg dose administered underfasted conditions.

FIG. 43 shows a linear scale graph comparing the mean plasmahydroxyitraconazole concentration over time in a study assessing therelative bioavailability of a 50 mg LOZANOC dose with a 100 mg dose ofSPORANOX® administered under fed conditions. Closed circles representthe 50 mg LOZANOC dose administered under fed conditions; open circlesrepresent the reference SPORANOX® 100 mg dose administered under fedconditions.

FIG. 44 shows a log-transformed scale graph comparing the mean plasmahydroxyitraconazole concentration over time in a study assessing therelative bioavailability of a 50 mg LOZANOC dose with a 100 mg dose ofSPORANOX® under fed conditions. Closed circles represent the 50 mgLOZANOC dose administered under fed conditions; open circles representthe reference SPORANOX® 100 mg dose administered under fed conditions.

FIG. 45 shows a Box-plot analysis by formulation of the combined fedstate and fasted state AUC(0-∞) data in Example 9.

FIG. 46 shows a Box-plot analysis of AUC(0-∞) in Example 9 byformulation in a fed state only.

FIG. 47 shows a Box-plot analysis of AUC(0-∞) in Example 9—Sporanox® 100mg capsules in a fed state versus 50 mg capsules of the solid oraldosage form of LOZANOC in a fasted state.

FIG. 48 shows a Box-plot analysis of AUC(0-∞) in Example 9 byformulation in a fasted state only.

FIG. 49 shows a Box-plot analysis of AUC(0-∞) in Example 10 byformulation—both occurrences combined.

FIG. 50 shows a Box-plot analysis of AUC(0-∞) in Example 10 byformulation—second occurrence only.

FIG. 51 is a plot showing the magnitude of within-subject variability ofAUC(0-∞) in Study 2-50 mg capsules of the solid oral dosage form ofLOZANOC versus Sporanox® 100 mg capsules.

FIG. 52 is a plot showing individual AUC(0-∞) values from Example 9 (fedstate).

FIG. 53 shows a linear scale graph comparing the mean plasmaitraconazole concentration over time in a study assessing thebioequivalence of two treatments of a 50 mg LOZANOC dose with a 100 mgdose of SPORANOX® administered under fed conditions. Closed circlesrepresent the 50 mg LOZANOC dose administered under fed conditions(Occurrence 1); open circles represent the 50 mg LOZANOC doseadministered under fed conditions (Occurrence 2); open squares representthe reference SPORANOX® 100 mg dose administered under fed conditions(Occurrence 1); closed squares represent the reference SPORANOX® 100 mgdose administered under fed conditions (Occurrence 2).

FIG. 54 shows a log-transformed scale graph comparing the mean plasmaitraconazole concentration over time in a study assessing thebioequivalence of two treatments of a 50 mg LOZANOC dose with a 100 mgdose of SPORANOX® administered under fed conditions. Closed circlesrepresent the 50 mg LOZANOC dose administered under fed conditions(Occurrence 1); open circles represent the 50 mg LOZANOC doseadministered under fed conditions (Occurrence 2); open squares representthe reference SPORANOX® 100 mg dose administered under fed conditions(Occurrence 1); closed squares represent the reference SPORANOX® 100 mgdose administered under fed conditions (Occurrence 2).

FIG. 55 is a graph which shows that the systemic exposure (based on AUCand Cmax) from the 50 mg SUBA® formulation was less variable betweendosing occurrences than that of the Sporanox® in the study assessing thebioequivalence of two treatments of a 50 mg dose of LOZANOC to a 100 mgdose of SPORANOX® when administered under fed conditions.

FIG. 56 shows a log-transformed scale graph comparing the mean plasmahydroxyitraconazole concentration over time in a study assessing thebioequivalence of two treatments of a 50 mg LOZANOC dose with a 100 mgdose of SPORANOX® administered under fed conditions. Closed circlesrepresent the 50 mg LOZANOC dose administered under fed conditions(Occurrence 1); open circles represent the 50 mg LOZANOC doseadministered under fed conditions (Occurrence 2); open squares representthe reference SPORANOX® 100 mg dose administered under fed conditions(Occurrence 1); closed squares represent the reference SPORANOX® 100 mgdose administered under fed conditions (Occurrence 2).

FIG. 57 shows a log-transformed scale graph comparing the mean plasmahydroxyitraconazole concentration over time in a study assessing thebioequivalence of two treatments of a 50 mg LOZANOC dose with a 100 mgdose of SPORANOX® administered under fed conditions. Closed circlesrepresent the 50 mg LOZANOC dose administered under fed conditions(Occurrence 1); open circles represent the 50 mg LOZANOC doseadministered under fed conditions (Occurrence 2); open squares representthe reference SPORANOX® 100 mg dose administered under fed conditions(Occurrence 1); closed squares represent the reference SPORANOX® 100 mgdose administered under fed conditions (Occurrence 2).

FIG. 58 is a graph which shows that SUBA™-Itraconazole was significantlysuperior to placebo for both efficacy endpoints, whereas SPORANOX®(itraconazole) was not significantly different to placebo. A comparisonof mycological, clinical, and therapeutic cure at Week 24. MycologicalCure was measured by negative stain and culture; clinical cure wasmeasured as a nail rating score of zero; therapeutic cure required bothmycological cure and clinical cure. The Nail Rating Score was determinedto be 0 if less than 10% of the nail is missing, and there is nothickening or discloration.

FIG. 59 is a graph illustrating illustrates the rates (%) of mycologicalcure, clinical cure, and complete cure for LOZANOC. The cure rates forLOZANOC at week 24 are comparable to terbinafine pulse therapy and arehigher than would be expected for conventional itraconazole. For allcomparisons, p<0.0001 except for clinical cure T₁₂ v I₃ where p<0.0015;T₁₂ v I₄ p=0.0022; and for complete cure T₁₂ v I₃ p=0.0007 and T₁₂ v I₄p=0.0044.

FIG. 60 is a graph showing individual subject AUC_(inf) results rankedin order of lowest to highest for both test and reference, with theminimum AUC thresholds arrived at in Table 80 superimposed. Thisillustrates the actual AUCs required for optimal therapeutic effect andcompares the relative performance of Lozanoc 50 mg hard capsules andSporanox® 100 mg Capsules in Example 10.

FIG. 61 is a graph showing individual subject AUC_(inf) results rankedin order of lowest to highest for both test and reference, with theminimum AUC thresholds arrived at in Table 80 superimposed. Thisillustrates the actual AUCs required for optimal therapeutic effect andcompares the relative performance of Lozanoc 50 mg hard capsules andSporanox® 100 mg Capsules in the first administration of Lozanocdescribed in Example 12 (see pharmacokinetics section).

FIG. 62 is a graph showing individual subject AUC_(inf) results rankedin order of lowest to highest for both test and reference, with theminimum AUC thresholds arrived at in Table 80 superimposed. Thisillustrates the actual AUCs required for optimal therapeutic effect andcompares the relative performance of Lozanoc 50 mg hard capsules andSporanox® 100 mg Capsules in the second administration of Lozanocdescribed in Example 12 (see pharmacokinetics section).

FIG. 63 shows the comparison of the individual AUC/MIC ratios forsubjects in the study described in Example 10 who received Lozanoc 50 mghard capsules in the fasted state versus Sporanox® 100 mg Capsules inthe fed state.

FIG. 64 shows the comparison of the individual AUC/MIC ratios forsubjects in the study described in Example 10 who received Lozanoc 50 mgHard Capsules in the fasted state versus the fed state.

DETAILED DESCRIPTION

It should be understood that singular forms such as “a,” “an,” and “the”are used throughout this application for convenience, however, exceptwhere context or an explicit statement indicates otherwise, the singularforms are intended to include the plural. Further, it should beunderstood that every journal article, patent, patent application,publication, and the like that is mentioned herein is herebyincorporated by reference in its entirety and for all purposes. Allnumerical ranges should be understood to include each and everynumerical point within the numerical range, and should be interpreted asreciting each and every numerical point individually. The endpoints ofall ranges directed to the same component or property are inclusive, andintended to be independently combinable.

Definitions

Except for the terms discussed below, all of the terms used in thisApplication are intended to have the meanings that one of skill in theart at the time of the invention would ascribe to them.

“About” includes all values having substantially the same effect, orproviding substantially the same result, as the reference value. Thus,the range encompassed by the term “about” will vary depending on contextin which the term is used, for instance the parameter that the referencevalue is associated with. Thus, depending on context, “about” can mean,for example, ±15%, ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, or ±less than 1%.Importantly, all recitations of a reference value preceded by the term“about” are intended to also be a recitation of the reference valuealone. Notwithstanding the preceding, in this application the term“about” has a special meaning with regard to pharmacokinetic parameters,such as area under the curve (including AUC, AUC_(t), and AUC_(∞))C_(max), T_(max), and the like. When used in relationship to a value fora pharmacokinetic parameter, the term “about” means from 80% to 125% ofthe reference parameter.

“Absorption profile” refers to the rate and extent of exposure of adrug, e.g., itraconazole, by data analysis of the AUC and/or Cmaxincluding the curves thereof.

“Administering” includes any mode of administration, such as oral,subcutaneous, sublingual, transmucosal, parenteral, intravenous,intra-arterial, buccal, sublingual, topical, vaginal, rectal,ophthalmic, otic, nasal, inhaled, and transdermal. “Administering” canalso include prescribing or filling a prescription for a dosage formcomprising a particular compound, such as itraconazole, as well asproviding directions to carry out a method involving a particularcompound or a dosage form comprising the compound. In particular, theadministration method can be oral administration.

“Bioequivalence” means the absence of a significant difference in therate and extent to which the active agent or surrogate marker for theactive agent in pharmaceutical equivalents or pharmaceuticalalternatives becomes available at the site of action when administeredin an appropriately designed study. For example, bioequivalence can bedefined by the definition promulgated by the U.S. Food and DrugAdministration or any successor agency thereof, such as the Federal DrugAdministration's guidelines and criteria, including “GUIDANCE FORINDUSTRY BIOAVAILABILITY AND BIOEQUVALENCE STUDIES FOR ORALLYADMINISTERED DRUG PRODUCTS—GENERAL CONSIDERATIONS” available from theU.S. Department of Health and Human Services (DHHS), Food and DrugAdministration (FDA), Center for Drug Evaluation and Research (CDER)March 2003 Revision 1; and “GUIDANCE FOR INDUSTRY STATISTICAL APPROACHESTO ESTABLISHING BIOEQUIVALENCE” DHHS, FDA, CDER, January 2001, both ofwhich are incorporated by reference herein in their entirety.Alternatively bioequivalence can be shown by Europe's EMEA guidelines,wherein the 90% CI limits for a ratio of the geometric mean oflogarithmic transformed AUC0-∞ and AUC0-t for the two products ormethods are about 0.80 to about 1.25. The 90% CI limits for a ratio ofthe geometric mean of logarithmic transformed Cmax for the two productsor methods can have a wider acceptance range when justified by safetyand efficacy considerations. For example the acceptance range can beabout 0.70 to about 1.43, specifically about 0.75 to about 1.33, andmore specifically about 0.80 to about 1.25.

“Co-administration” refers to administration of two or more differentactive agents together in a coordinated manner. Co-administrationincludes administration of two or more different active agentssimultaneously, sequentially, or separately. Thus, “co-administration”includes administration in the same or different dosage forms,concurrent administration, as well as administration that is notconcurrent, such as administration of a first active agent followed oralternated with administration of a second active agent as part of acoordinated plan for treatment.

A “composition” is a collection of materials containing the specifiedcomponents. One or more dosage forms may constitute a composition, solong as those dosage forms are associated and designed for use together.For example, a composition comprising about 50 mg of itraconazoleincludes two unit dosage forms having about 25 mg of itraconazole eachif the two dosage forms are designed to be administered together or atapproximately the same time to the same subject.

“Enteric polymer” refers to a polymer that is poorly soluble in aqueousmedium at a pH of about 4.5 or less, but becomes soluble in aqueousmedium at a pH of greater than about 5. For example, an enteric polymeris poorly soluble in gastric juice, but is soluble in the lower GI tractenvironment.

“Itraconazole” is a common name for a triazole antifungal compound, thespecific chemical structure and IUPAC name of which are well known inthe art. It is available commercially (see Merck Index Reg. No. 5262(12th ed. 1996) and U.S. Pat. No. 4,267,179). As used herein,“itraconazole” includes not only the chemical compound (free base form,also referred to as “free itraconazole”), but also all optical isomers,such as enantiomers, diastereomers, meso compounds, and the like, aswell as pharmaceutically acceptable salts, solvates, and prodrugs (suchas esters) thereof.

“Pharmaceutical composition” refers to a formulation of a compound ofthe disclosure, such as itraconazole, and a medium generally accepted inthe art for the delivery of the biologically active compound to mammals,e.g., humans. Such a medium includes all pharmaceutically acceptablecarriers, diluents or excipients therefor. The pharmaceuticalcomposition may be in various dosage forms or contain one or more unitdose formulations.

“Pharmaceutically acceptable” means suitable for use in contact with thetissues of humans and animals without undue toxicity, irritation,allergic response, and the like, commensurate with a reasonablebenefit/risk ratio, and effective for their intended use within thescope of sound medical judgment.

A “reference composition of itraconazole” (reference composition) is acomposition comprising itraconazole that exhibits one or more of (1) hasa AUC_(t) in the fasted state that is about 35% or more lower than theAUC_(t) in the fed state; (2) has an intra-subject variability of about30% or greater; and (3) about 100 mg of itraconazole or more. Particularreference compositions include those with about 100 mg of itraconazoleor more. Other particular reference compositions include those that donot include a solid solution or solid dispersion of itraconazole in anacid resistant polymeric carrier. One exemplary particular referencecomposition contains a blend of itraconazole, and one or moreexcipients, such as diluents, carriers, fillers, disintegrants, and thelike. Another exemplary particular reference composition contains 100 mgof itraconazole, sugar spheres, hydroxypropyl methyl cellulose, andpolyethylene glycol, such as polyethylene glycol 20000, in a gelatincapsule shell. For example, and most particularly, the reference dosageform can be a capsule commercially available under the name SPORANOX®.

“Salts” include derivatives of an active agent, wherein the active agentis modified by making acid or base addition salts thereof. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid addition salts of basic residues such as amines;alkali or organic addition salts of acidic residues; and the like, or acombination comprising one or more of the foregoing salts. Thepharmaceutically acceptable salts include salts and the quaternaryammonium salts of the active agent. For example, acid salts includethose derived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; other acceptableinorganic salts include metal salts such as sodium salt, potassium salt,cesium salt, and the like; and alkaline earth metal salts, such ascalcium salt, magnesium salt, and the like, or a combination comprisingone or more of the foregoing salts. Pharmaceutically acceptable organicsalts includes salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, mesylic, esylic, besylic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, HOOC—(CH₂)_(n)—COOH where n is 0-4, andthe like; organic amine salts such as triethylamine salt, pyridine salt,picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, and the like;and amino acid salts such as arginate, asparginate, glutamate, and thelike; or a combination comprising one or more of the foregoing salts.

“Solvate” means a complex formed by solvation (the combination ofsolvent molecules with molecules or ions of the active agent of thepresent invention), or an aggregate that consists of a solute ion ormolecule (the active agent of the present invention) with one or moresolvent molecules. For example, a solvate where the solvent molecule ormolecules are water is called a hydrate. Hydrates are particularlycontemplated as solvates of the materials described herein.

“Solid dispersion” relates to a solid system comprising a nearlyhomogeneous or homogeneous dispersion of an active ingredient, such asitraconazole, in an inert carrier or matrix.

“Substantially similar to” means having a great extent or degree oflikeness to the reference item, term, quantity, etc.

“Prodrug” refers to a precursor of the active agent wherein theprecursor itself may or may not be pharmaceutically active but, uponadministration, will be converted, either metabolically or otherwise,into the active agent or drug of interest. For example, prodrug includesan ester or an ether form of an active agent.

“Therapeutically effective amount” or “effective amount” refers theamount of a pharmaceutically active agent, such as itraconazole, that,when administered to a patient for treating a disease according to thedosing regimen as described herein, is sufficient to effect suchtreatment for the disease. The “therapeutically effective amount” willvary depending on the disease and its severity, and the age, weight, andother conditions of the patient to be treated.

A composition or dosage form is “therapeutically equivalent” to areference composition or dosage form if it has a therapeutic effect thatis substantially similar to the therapeutic effect of the referencecomposition or dosage form, for example, therapeutically equivalentdosage forms can have substantially similar efficacy towards aparticular disease or condition when administered over a substantiallysimilar time period.

“Treating” includes ameliorating, mitigating, and reducing the instancesof a disease or condition, or the symptoms of a disease or condition, inaddition to providing directions or prescribing a drug for such purpose.

“Patient” or “subject” refers to a mammal, e.g., a human, in need ofmedical treatment.

Particular pharmacokinetic parameters are defined in Table 1.

TABLE 1 Parameter Definition AUC_(0-tlast) Area under the plasmaconcentration-time curve from time zero up to the last quantifiableconcentration AUC_(0-∞) Area under the plasma concentration-time curvefrom time zero to infinity % AUC_(extrap) Percentage of AUC that is dueto extrapolation from t_(last) to infinity C_(max) Maximum observedplasma concentration t_(max) Time of the maximum observed plasmaconcentration t_(lag) Time before the start of absorption t_(last) Timeof the last quantifiable plasma concentration t_(1/2) Apparent plasmaterminal elimination half-life CL/F Apparent total plasma clearance(itraconazole only) V_(z)/F Apparent volume of distribution during theterminal phase (itraconazole only) MR_(AUC) Metabolic ratio based on AUC(hydroxyitraconazole only) MR_(Cmax) Metabolic ratio based on C_(max)(hydroxyitraconazole only)

It is noted that AUC_(0-t) and AUC_(0-tlast) are used interchangeablyherein. Also, AUC_(inf) and AUC_(t-inf) are used interchangeably withAUC_(0-∞). It should also be understood that, unless otherwisespecified, all pharmacokinetic parameters are measured after a singleadministration of the specified amount of itraconazole followed by awashout period in which no additional itraconazole is administered.

Pharmaceutical Composition Comprising Itraconazole

A composition comprising itraconazole can comprise a therapeuticallyamount of itraconazole and less than 75 mg of itraconazole, such asabout 50 mg to about 65 mg of itraconazole. Particular compositions cancomprise about 50 mg of itraconazole. Other particular compositions cancomprise about 65 mg of itraconazole.

When administered to a subject in the fed state, a composition, such asany described herein, and particular a composition comprising about 50mg of itraconazole, can exhibit certain pharmacokinetic parameters. Forexample, when administered to a subject in the fed state, thecomposition can exhibit an AUC_(0-t) of about 440 ng hr/mL or higher,such as from about 440 ng hr/mL to about 740 ng hr/mL, about 440 nghr/mL to about 700 ng hr/mL, or about 448 ng hr/mL to about 676 nghr/mL. In particular, when administered to a subject in the fed state,the composition can exhibit an AUC_(0-t) from about 475 to about 625 nghr/mL. Even more particularly, when administered to a subject in the fedstate, the composition can exhibit an AUC_(0-t) from about 500 to about600 ng hr/mL. Thus, the ratio of AUC_(0-t) (in ng hr/mL) administered ina fed state to itraconazole mass (in mg) can be about 8.8 or higher,such as from about 8.8 to about 14.8, about 8.8 to about 14.0, about 9.0to about 13.6, about 9.5 to about 12.5, or about 10.0 to about 12.0.

A composition, including any dosage form described herein, andparticularly a composition comprising about 50 mg of itraconazole, canalso have a particular AUC_(0-t) when administered to a subject in thefasted state. For example, when administered to a subject in the fastedstate, the AUC_(0-t) can be about 350 ng hr/mL or higher, such as fromabout 350 to about 620 ng hr/mL, about 355 to about 550 ng hr/mL, orabout 359 to about 534 ng hr/mL. In particular, when administered to asubject in the fasted state, the AUC_(0-t) can be from about 375 toabout 515 ng hr/mL. Even more particularly, when administered to asubject in the fasted state, the AUC_(0-t) can be from about 400 toabout 500 ng hr/mL. Thus, the ratio of AUC_(0-t) (in ng hr/mL) whenadministered to a subject in the fasted state to mass of itraconazole(in mg) can be about 7.0 or higher, such as from about 7.0 to about12.4, about 7.1 to about 11.0, about 7.0 to about 10.7, about 7.5 toabout 10.3, or about 8.0 to about 10.0.

A composition, including any described herein, and particularly acomposition comprising about 50 mg of itraconazole, can have aparticular AUC_(inf) when administered to a subject in the fed state.For example, the AUC_(inf), when administered to a subject in the fedstate, can be about 575 ng hr/mL or higher, such as about 590 to about750 ng hr/mL. Particularly, the AUC_(inf), when administered to asubject in the fed state, can be about 591 to about 736 ng hr/mL, suchas about 600 to about 725 ng hr/m. Even more particularly, the AUCinf,when administered to a subject in the fed state, can be about 625 toabout 700 ng hr/mL. Thus, the ratio of AUC_(inf) when administered to asubject in the fed state (in ng hr/mL) to mass of itraconazole (in mg)can be about 11.5 or higher, such as about 11.8 to about 15, about 12 toabout 14.5, or about 12.5 to about 14.

A composition, including any described herein, and particularly acomposition comprising about 50 mg of itraconazole, can have aparticular AUC_(inf) when administered to a subject in the fasted state.For example, the AUC_(inf), when administered to a subject in the fastedstate, can be about 500 ng hr/mL or higher, such as about 521 ng hr/mLto about 611 ng hr/mL. Particularly, the AUC_(inf), when administered toa subject in the fasted state, can be about 550 ng hr/mL to about 600 nghr/mL. Thus, the ratio of AUC_(inf) when administered to a subject inthe fasted state (in ng hr/mL) to mass of itraconazole (in mg) can beabout 10 or higher, such as about 10.4 to about 12.22, or about 11.0 toabout 12.0.

A composition, including any described herein, and particularly a dosageform comprising about 50 mg of itraconazole, can have a particularC_(max) when administered to a subject in the fed state. For example,when administered to a subject in the fed state, the Cmax can be about60 ng/mL or higher, such as from about 60 to about 75 ng/mL or about 63to about 75 ng/mL. In particular, when administered to a subject in thefed state, the C_(max) can be from about 65 to about 70 ng/mL.

A composition, including any described herein, and particularly a dosageform comprising about 50 mg of itraconazole, can have a particularC_(max) when administered to a subject in the fasted state. For example,when administered to a subject in the fasted state, the C_(max) can beabout 30 ng/mL or higher, such as about 30 ng/mL to about 60 ng/mL orabout 32 ng/mL to about 55 ng/mL. In particular, when administered to asubject in the fasted state, the C_(x) can be from about 37 ng/mL toabout 52 ng/mL or about 35 ng/mL to about 50 ng/mL. More particularly,when administered to a subject in the fasted state, the C_(max) can befrom about 40 ng/mL to about 50 ng/mL or about 42 ng/mL to about 50ng/mL.

A composition, including any described herein, and particularly a dosageform comprising about 65 mg of itraconazole can have a particularAUC_(0-t) when administered to a subject in the fed state. For example,the AUC_(0-t), when administered to a subject in the fed state, can beabout 650 ng hr/mL or greater, such as about 650 to about 1200 ng hr/mLor about 671 to about 1172 ng hr/mL. Particularly, the AUC_(0-t), whenadministered to a subject in the fed state, can be about 700 to about950 ng hr/mL. Even more particularly, the AUC_(0-t), when administeredto a subject in the fed state, can be about 750 to about 850 ng hr/mL.Thus, the ratio of AUC_(0-t) (in ng hr/mL) when administered to asubject in the fed state to mass of itraconazole (in mg) can be about10.0 or higher, such as about 10.3 to about 18.0, about 10.8 to about14.6, or about 11.5 to about 13.0.

A composition, including any described herein, and particularly a dosageform comprising about 65 mg of itraconazole, can have a particularAUC_(0-t) when administered to a subject in the fasted state. Forexample, the AUC_(0-t), when administered to a subject in the fastedstate, can be about 450 ng hr/mL or greater, such as about 450 to about900 ng hr/mL, about 485 to about 900 ng hr/mL, or about 500 to about 885ng hr/mL. Particularly, the AUC_(0-t), when administered to a subject inthe fasted state, can be about 525 to about 725 ng hr/mL. Even moreparticularly, the AUC_(0-t), when administered to a subject in thefasted state, can be about 600 to about 700 ng hr/mL. Thus, the ratio ofAUC_(0-t) (in ng hr/mL) when administered to a subject in the fastedstate to the mass of itraconazole (in mg) can be about 7.5 or greater,such as about 7.5 to about 13.6, about 7.7 to about 13.6, about 801 toabout 11.2, or about 9.2 to about 10.8.

A composition, including any described herein, and particularly a dosageform comprising about 65 mg of itraconazole, can have a particularAUC_(inf) when administered to a subject in the fed state. For example,the AUC_(inf), when administered to a subject in the fed state, can beabout 800 ng hr/mL or greater, such as about 811 ng hr/mL to about 1,400ng hr/mL. In particular, the AUC_(inf), when administered to a subjectin the fed state, can be about 850 ng hr/mL to about 1,200 ng hr/mL.Even more particularly, the AUC_(inf), when administered to a subject inthe fed state, can be about 900 ng hr/mL to about 1,000 ng hr/mL, orabout 850 to about 950 ng hr/mL. Thus, the ratio of the AUC_(inf) (in nghr/mL) when administered to a subject in the fed state to the mass ofitraconazole (in mg) can be about 12.3 or greater, such as, about 12.3to about 21.5, about 12.5 to about 21.5, about 13.1 to about 18.5, about13.9 to about 15.4, or about 13.1 to about 14.6.

A composition, including any described herein, and particularly a dosageform comprising about 65 mg of itraconazole, can have a particularAUC_(inf) when administered to a subject in the fasted state. Forexample, the AUC_(inf), when administered to a subject in the fastedstate, can be about 600 ng hr/mL or greater, such as about 610 ng hr/mLto about 1,050 ng hr/mL. In particular, the AUC_(inf), when administeredto a subject in the fasted state, can be about 640 ng hr/mL to about 900ng hr/mL. Even more particularly, the AUC_(inf), when administered to asubject in the fasted state, can be about 675 ng hr/mL to about 750 nghr/mL, or about 625 to about 800 ng hr/mL. Thus, the ratio of AUC_(inf)(in ng hr/mL when administered to a subject in the fasted state to themass of itraconazole (in mg) can be about 9.2 or greater, such as about9.2 to about 16.2, about 9.4 to about 16.2, about 9.8 to about 13.8,about 10.4 to about 12.3, or about 9.6 to about 11.5.

A composition, including any described herein, and particularly a dosageform comprising about 65 mg of itraconazole, when administered to asubject in the fed state, can have a C_(max) of about 65 ng/mL orhigher, such as about 85 ng/mL to about 100 ng/mL. Particularly, whenadministered to a subject in the fed state, the C_(max) can be about 70ng/mL to about 80 ng/mL. Thus the ratio of C_(max) (in ng/mL) whenadministered to a subject in the fed state to the mass of itraconazole(in mg) can be about 1.00 or greater, such as about 1.00 to about 1.54about 1.31 to about 1.54, or about 1.08 to about 1.23.

A composition, including any described herein, and particularly a dosageform comprising about 65 mg of itraconazole, when administered to asubject in the fasted state, can have a C_(max) of about 35 ng/mL orhigher, such as about 35 ng/mL to about 70 ng/mL. Particularly, whenadministered to a subject in the fasted state, the Cmax can be about 40ng/mL to about 65 ng/mL. Thus the ratio of C_(max) (in ng/mL) whenadministered to a subject in the fasted state to the mass ofitraconazole (in mg) can be about 0.54 or greater, such as about 0.54 toabout 1.08, or about 0.62 to about 1.00.

The present composition comprising itraconazole can also comprise one ormore excipients. The excipients can include one or more of waxes,polymers, binders, fillers, disintegrants, glidants, and the like. Thepolymers can include any pharmaceutically acceptable polymer, such asone or more hydrophilic polymers; one or more non-gelling polymers; oneor more acid-resistant polymers and enteric polymers; one or moreosmopolymers; one or more film-forming, water insoluble polymers; one ormore film-forming, water soluble polymers; or combinations thereof. Thewaxes can include one or more of beeswax, spermaceti, lanolin, carnaubawax, candelilla wax, ouricury wax, sugercane wax, retamo wax, jojobaoil, epicuticula waxes, paraffin, montan wax, waxes produced fromcracking polyethylene, microcrystalline wax, petroleum jelly, and thelike.

Binders can include any one or more of saccharides, such as sucrose,lactose, mannose, trehaolse, fructose, starches, cellulose,microcrystalline cellulose, methyl cellulose, ethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, and the like,gelatin, polyvinylpyrrolidone, polyethylene glycol, and the like.

Disintegrants can include one or more of crospovidone, croscarmellose,such as crosscarmellose sodium, polyvinylpyrrolidone, methyl cellulose,microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, such as hydroxypropyl methyl cellulose and hydroxypropylethyl cellulose, starch, pregelatinised starch, sodium alginate, andsodium starch glycolate, for example, sodium starch glycolate.

Fillers can include one or more of cellulose, microcrystallinecellulose, dibasic calcium phosphate, monobasic calcium phosphate,lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, andthe like.

Polymers can include any pharmaceutically acceptable polymer. Thepolymer can be formulated with the active compound (e.g., itraconazole)and one or more additional excipients in various forms. For example, thepresent composition may be formulated to a matrix system, an osmoticdelivery system, or a multiparticulate system. As used herein, the term“matrix” denotes a homogeneous solid mixture composed of evenlydispersed ingredients throughout. In one embodiment, the matrix systemis a solid solution or solid dispersion as described herein.

In one embodiment of the osmotic delivery system, the compositioncomprises a release rate controlling membrane disposed over a pull layerand an osmotic push layer, wherein the pull layer comprisesitraconazole, and the release rate controlling membrane has an orificeimmediately adjacent to the pull layer. The pull layer furtheroptionally comprises a release rate controlling polymer and/or apharmaceutically acceptable excipient. The release rate controllingmembrane is a semipermeable wall that surrounds the pull layer and theosmotic push layer. The wall is permeable to the passage of fluid andhas an orifice which allows passage of itraconazole, from inside of thewall to outside. Upon being exposed to biological or other fluids, thesemipermeable wall allows permeation of the fluids through the wallcausing expansion of the osmotic push layer, and consequently theosmotic push layer pushes the pull layer through the orifice. Therelease rate of itraconazole, is determined by the permeability of thewall and the osmotic pressure gradient across the wall. In oneembodiment, the osmotic push layer comprises an osmopolymer. In oneembodiment, the pull layer further comprises an osmagent, also known asosmotically effective solutes. The osmagent can be any compound,inorganic or organic, that exhibit an osmotic pressure gradient acrossan external fluid across the semipermeable wall.

Certain examples of the multiparticulate delivery system and themanufacturing thereof are described in detail in Lu, Int. J. Pharm.,1994, 112, pages 117-124, the content of which is herein incorporated byreference in its entirety. In one embodiment, the composition comprisesone or more particles and each of the particles comprises an active corecomprising itraconazole; and a release rate controlling polymer disposedover the core. In another embodiment, the composition comprises one ormore particles and each of the particles comprises an inert core, anactive layer comprising itraconazole disposed over the inert core, and arelease rate controlling polymer disposed over the active layer. Inanother embodiment, the composition comprises an inert core, and acoating disposed over the inert core, wherein the coating comprisesitraconazole. Any of the active core, the inert core, the active layer,the coating, or the coating formed by the release rate controllingpolymer disposed over the active layer may optionally further comprise apharmaceutically acceptable excipient. In one embodiment of themultiparticulate delivery system, the release rate controlling polymercomprises a film-forming, water insoluble polymer in combination with afilm-forming, water soluble polymer. The ratio between the waterinsoluble polymer and the water soluble polymer can be adjusteddepending on the intended drug release profile.

“Hydrophilic polymer” refers to a polymer having a strong affinity forwater and tending to dissolve in, mix with, or be wetted by water.Examples of the hydrophilic polymer include, but are not limited topolyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, sodium carboxymethylcellulose,calcium carboxymethyl cellulose, methyl cellulose, polyacrylic acid,maltodextrin, pre-gelatinized starch, guar gum, sodium alginate,polyvinyl alcohol, chitosan, locust bean gum, amylase, any otherwater-swelling polymer, and a combination thereof.

By “non-gelling polymer”, it is meant a polymer that only swellsslightly or does not swell to form a gel when exposed to an aqueousmedium. Exemplary non-gelling polymers include cellulose acetatephthalate (e.g., powder: pH 6.2, available from Eastman Chemical Co. asC-A-P; Dispersion: pH: 6.0, available from FMC BioPolymer as AquaCoat®CPD), cellulose acetate succinate (e.g., LF: pH 5.5; MF: pH 6.0; HF: pH6.8; LG; pH 5.5; MG: pH 6.0; HG: 6.8, F grades are an aqueous dispersionand G grades are from solvent available from Shin-Etsu under the tradename AQOAT®), hypromellose phthalate (HPMCP) (e.g., Grade HP-50: pH 5.0;Grade HP-55: pH 5.5 available from Shin-Etsu), hypromellose acetatesuccinate (HPMCAS), polyvinylacetate phthalate (e.g., aqueousdispersion: pH 5.0; Powder: pH 5.0 available from Colorcon, the aqueousdispersion under the trade name Sureteric® and the powder under thetrade name Opadry® Enteric), hydroxyethyl cellulose phthalate, celluloseacetate maleate, cellulose acetate trimellitate, cellulose acetatebutyrate, cellulose acetate propionate, methacrylic acid-methylmethacylate co-polymers (e.g., Type A: pH 6.0; Type B: pH 7.0 bothavailable from Degussa/Evonik with the trade names EUDRAGIT® L 100 forType A and EUDRAGIT® S 100 for Type B), methacrylic acid-ethylacrylateco-polymers (available under the trade name EUDRAGIT® L, e.g., L100-55),methacrylic acid-methyl acrylate-methyl methacrylate co-polymers(available under the trade name EUDRAGIT® FS-30D for delivery above pH7.0), and the like or combinations comprising at least one of theforegoing. Methacrylic acid-methyl methacylate co-polymers, methacrylicacid-ethylacrylate co-polymers, and/or methacrylic acid-methylacrylate-methyl methacrylate co-polymers are also known aspolymethacrylates as described in the Handbook of PharmaceuticalExcipients, 2006, the Fifth Edition, edited by Raymond C Rowe, Paul J.Sheskey, and Sian C Owen, pages 553 to 560, the content of which isincorporated by references in its entirety. EUDRAGIT® is a trademark ofEvonik Industries. The specifications for various EUDRAGIT® productsincluding the above-mentioned ones can be found in the manufacture'sproduct manual or on the website for the corresponding EUDRAGIT®product, the content of which is incorporated by references in itsentirety.

The osmopolymers are typically hydrophilic polymers and interact withwater and aqueous biological fluids and swell or expand to push a drugcomposition through the orifice. The osmopolymers exhibit the ability toswell in water and retain a significant portion of the imbibed waterwithin the polymer structure. The osmopolymers may swell or expand to avery high degree. The osmopolymers can be noncross-linked orcross-linked. The swellable, hydrophilic polymers may be lightlycross-linked, such as cross-links being formed by covalent or ionicbonds. The osmopolymers can be of plant, animal or synthetic origin.Hydrophilic polymers suitable for the present purpose include, but arenot limited to poly(hydroxyalkylmethacrylate) having a molecular weightof from 30,000 to 5,000,000; poly(vinylpyrrolidone) having molecularweight of from 10,000 to 360,000; anionic and cationic hydrogels;polyelectrolyte complexes, poly(vinyl alcohol) having a low acetateresidual, cross-linked with glyoxal, formaldehyde, or glutaraldehyde andhaving a degree of polymerization from 200 to 30,000; a mixture ofmethyl cellulose, cross-linked agar and carboxymethyl cellulose; a waterinsoluble, water swellable copolymer reduced by forming a dispersion offinely divided copolymer of maleic anhydride with styrene, ethylene,propylene, butylene or isobutylene cross-linked with from 0.00001 toabout 0.5 moles of polyunsaturated cross-linking agent per mole ofmaleic anhydride in the copolymer; water swellable polymers of N-vinyllactams, and the like. Other osmopolymers include hydrogel polymers,such as Carbopol (acrylic acid-based polymers crosslinked withpolyalkylene polyethers) and the sodium salt thereof; acidic carboxypolymers generally having a molecular weight of 450,000 to 4,000,000 andtheir metal salts; Polyox; polyethylene oxide polymers having amolecular weight of 100,000 to 7,500,000.

Examples of the film-forming, water insoluble polymer include, but arenot limited to ethylcellulose, cellulose acetate, cellulose propionate(lower, medium or higher molecular weight), cellulose acetatepropionate, cellulose acetate butyrate, cellulose acetate phthalate,cellulose triacetate, poly(methyl methacrylate), poly(ethylmethacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate),poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(laurylmethacrylate), poly(phenyl methacrylate), poly(methyl acrylate),poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecylacrylate), poly(ethylene), poly(ethylene) low density, poly(ethylene)high density, poly(propylene), poly(ethylene oxide), poly(ethyleneterephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate),poly(vinyl chloride) or polyurethane, or any other water insolublepolymer, or mixtures thereof.

Examples of the film-forming, water soluble polymer include, but are notlimited to polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose,hydroxypropyl cellulose, hydroxypropylmethyl cellulose and polyethyleneglycol, Pluronic F108, Pluronic F127, Pluronic F68 or mixtures thereof.

The present composition may be formulated to a matrix system. Thecomposition comprising itraconazole can comprise a solid solution orsolid dispersion, for example, a solid dispersion, of itraconazole in apharmaceutically acceptable carrier. The pharmaceutically acceptablecarrier can be a polymer. Exemplary polymers include acid-resistantpolymers and enteric polymers, although other polymers can also be used.Acid-resistant polymers can include polymers that are insoluble in waterat any pH and polymers that are insoluble in water at an acidic pH, suchas enteric polymers. Exemplary acid-resistant polymers includehydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate,hydroxypropyl methylcellulose acetate, such as hydroxypropylmethylcellulose acetate succinate, alginate, poly(meth)acrylic acidhomopolymers and copolymers, carbomers, carboxymethyl cellulose,carboxymethyl cellulose, methacrylic acid copolymers, shellac, celluloseacetate phthalate, hydroxypropyl cellulose acetate phthalate, celluloseacetate terephthalate, methyl cellulose acetate phthalate, celluloseacetate isophthalate, cellulose acetate trimellitate, EUDRAGIT® polymers(copolymers of one or more of poly(meth)acrylates, poly(meth)acrylicesters, and poly(meth)acrylamides), and the like. A particular exemplaryacid-resistant polymer is hydroxypropyl methylcellulose phthalate.

Exemplary enteric polymers include one or more of hydroxypropylmethylcellulose phthalate; polyvinyl acetate phthalate;hydroxypropylmethylcellulose acetate succinate; alginate; carbomer;carboxymethyl cellulose; methacrylic acid copolymer; shellac; celluloseacetate phthalate; starch glycolate; polacrylin; cellulose acetatephthalate; methyl cellulose acetate phthalate; hydroxypropylcelluloseacetate phthalate; cellulose acetate terephthalate; cellulose acetateisophthalate; and cellulose acetate trimellitate. A particular entericpolymer is hydroxypropyl methylcellulose phthalate, which iscommercially available from Shin-Etsu Chemical Industry Co Ltd under thetrade names HP-50, HP-55, and HP-55S.

A composition comprising itraconazole can comprise a solid solution orsolid dispersion, for example, a solid dispersion, of itraconazole in apharmaceutically acceptable carrier. The pharmaceutically acceptablecarrier can be a polymer, such as an acid-resistant polymer or anenteric polymer, particularly the acid-resistant polymers discussedherein, or the enteric polymers discussed herein, and, for example, moreparticularly hydroxypropyl methylcellulose phthalate, which iscommercially available from Shin-Etsu Chemical Industry Co Ltd under thetrade names HP-50, HP-55, and HP-55S.

The solid solution or solid dispersion can be made by methods known inthe art, for example, by methods disclosed in U.S. Pat. No. 6,881,745,which is hereby incorporated by reference in its entirety and for allpurposes. For example, a solid solution or solid dispersion can be madeby dissolving or dispersing the pharmaceutically acceptable carrier andthe itraconazole in a suitable solvent and then removing the solvent.The suitable solvent can be, for example, one or more of methylenechloride, chloroform, ethanol, methanol, propan-2-ol, ethyl acetate,acetone, water, and mixtures thereof. A particular solvent is methylenechloride.

Removing the solvent can be accomplished by evaporation, spray drying,lyophilizing, and the like. Removing the solvent can also beaccomplished by allowing the itraconazole and pharmaceuticallyacceptable carrier to co-precipitate or co-crystallize out of solution,followed by one or more of filtration, decanting, centrifuging, and thelike.

Other methods of forming solid solutions or solid dispersions includeco-grinding, melt extrusion, freeze drying, rotary evaporation, andother solvent removal processes.

The composition comprising itraconazole can comprise a therapeuticallyeffective amount of free itraconazole. When the itraconazole is in theform of a solid dispersion, the solid dispersion can be present insufficient amounts to provide a therapeutically effective amount ofitraconazole. The therapeutically effective amount of itraconazole,which in the case of a salt, solvate, ester, or the like is measured bythe amount of free itraconazole, can be less than about 100 mg, forexample, less than about 70 mg. Exemplary amounts of free itraconazolefor a single dosage form include about 48 mg to about 68 mg, such asabout 50 mg to about 65 mg, for instance about 50 mg to about 65 mg, forexample, about 50 mg or about 65 mg.

The weight ratio of the free itraconazole in the solid solution or soliddispersion to the pharmaceutically acceptable carrier, such ashydroxypropyl methylcellulose phthalate, can be from about 3:1 to about1:20, such as about 3:1 to about 1:5, about 1:1 to about 1:3, or about1:1.5, based on the weight of free itraconazole. Thus, thepharmaceutically acceptable carrier, such as hydroxypropylmethylcellulose phthalate, can be present from about 15 mg to about1,360 mg, for example, from about 15 mg to about 340 mg, about 48 toabout 204 mg, or particularly about 72 to about 102 mg, for example,about 75 mg or about 97.5 mg.

The composition comprising a solid dispersion of itraconazole canfurther comprise one or more additional pharmaceutically acceptableexcipients. When present, the one or more additional pharmaceuticallyacceptable excipients can be in the solid solution or dispersion, oroutside of the solid solution or dispersion, such as admixed or blendedwith the solid solution or dispersion. The one or more additionalpharmaceutically acceptable excipients can include one or moredisintegrants, one or more diluents, one or more fillers, one or morecolorants, one or more flavorants, one or more binders, one or moreglidants, one or more lubricants, one or more surface active agents, andmixtures thereof.

Exemplary disintegrants include one or more of crospovidone,croscarmellose, such as crosscarmellose sodium, polyvinylpyrrolidone,methyl cellulose, microcrystalline cellulose, lower alkyl-substitutedhydroxypropyl cellulose, such as hydroxypropyl methyl cellulose andhydroxypropyl ethyl cellulose, starch, pregelatinised starch, sodiumalginate, and sodium starch glycolate, for example, sodium starchglycolate. The disintegrant is often present outside of solid solutionor solid dispersion, and the weight ratio of the solid solution to soliddispersion can be from about 1:1 to about 1:10, such as about 2:1 toabout 6:1, about 4:1 to about 5:1, for example, from about 4.2:1,although this is not required unless otherwise specified. For example,when the dosage form is a tablet, the dosage form can comprise fromabout 1% to about 25% of disintegrant by weight.

Exemplary colorants include one or more of titanium dioxide and fooddyes.

Exemplary flavors include one or more of cinnamon oil, wintergreen oil,peppermint oil, bay oil, anise oil, eucalyptus oil, thyme oil, vanilla,such as tincture of vanilla, citrus oil, such as one or more of lemon,orange, lime, and grapefruit oil, and essences of fruits, such asessence of one or more of apple, banana, pear, peach, strawberry,raspberry, cherry, plum, pineapple, and apricot.

Exemplary lubricants include one or more of hydrogenated vegetable oil,magnesium stearate, sodium lauryl sulfate, magnesium lauryl sulfate,colloidal silica, and talc. In some examples, the lubricant is magnesiumstearate. In other examples, the lubricant is colloidal silica. In yetother examples, the lubricant is a mixture of magnesium stearate andcolloidal silica.

Exemplary glidants include one or more of silicon dioxide and talc.

Exemplary binders include one or more of microcrystalline cellulose,gelatin, sugars, such as one or more of mannitol, lactose, andcellulose, polyethylene glycol, gums, such as one or more of xanthan gumand guar gum, polyvinylpyrrolidone, pregelatinised starch, hydroxypropylcellulose, and hydroxypropylmethylcellulose.

Exemplary diluants include one or more of lactose, such as one or moreof lactose monohydrate, spray-dried lactose monohydrate, and anhydrouslactose, mannitol, xylitol, dextrose, sucrose, sorbitol,microcrystalline cellulose, starch, and calcium phosphate, such asdibasic calcium phosphate dihydrate.

Exemplary surface active agents include one or more of sodium laurylsulfate, polyethylene glycol, and polysorbate 80.

The composition can be, for example, in the form of one or more dosageforms, such as one or more of a powder, sachet, tablet, capsule, pill,suppository, implant, wafer, cream, ointment, syrup, gel, suspension,and the like. When the dosage form is a capsule, the capsule shell canbe a hard capsule shell, such as a gelatin shell, comprising the solidsolution or solid dispersion of itraconazole and the pharmaceuticallyacceptable carrier. The capsule shell can also comprise one or more ofthe additional pharmaceutically acceptable excipients discussed above,although that is not required unless otherwise specified. The capsuleshell can be a sufficient size to accommodate the contents of thecapsule.

An exemplary capsule can be filled with a solid dispersion thatcomprises about 50 mg itraconazole (based on the weight of freeitraconazole) and about 75 mg hydroxypropyl methylcellulose phthalate,and, as additional pharmaceutical excipients not part of the dispersion,about 30 mg sodium starch glycolate, about 1 mg to about 2 mg colloidalsilica, and about 1 mg to about 2 mg magnesium stearate. Anotherexemplary capsule can comprise about 65 mg itraconazole (based on theweight of free itraconazole), about 97.5 mg hydroxypropylmethylcellulose phthalate, and, as additional pharmaceutical excipientsnot part of the dispersion, about 39 mg sodium starch glycolate, about1.3 mg to about 2.6 mg colloidal silica, and about 1.3 mg to about 2.6mg magnesium stearate.

When the dosage form is a tablet, the tablet can comprise the solidsolution or solid dispersion of itraconazole and pharmaceuticallyacceptable carrier such that the itraconazole is from about 1% to about80%, such as about 5% to about 60%, by weight, of the tablet.

The tablet can also comprise one or more lubricant, such as the one ormore lubricants discussed above. The one or more lubricant can bepresent from about 0.25% to about 10% by weight of the tablet.

The tablet can further comprise one or more disintegrants, such as oneof more of the disintegrants discussed above. The one or moredisintegrant can be present from about 1% to about 25% by weight of thetablet.

The tablet can further comprise one or more glidants, such as one ormore of the glidants discussed above. The one or more glidants can bepresent from about 0.2% to about 1% by weight of the tablet.

The tablet can further comprise one or more surface active agents, suchas one or more of the surface active agents discussed above. The one ormore surface active agents can be present from about 0.2% to about 5% byweight of the tablet.

When the dosage form is a capsule, the capsule can comprise atherapeutically effective amount of itraconazole, such as the amountsdiscussed above. The remainder of the capsule can be filled withadditional pharmaceutical excipients, such as those discussed above.

The composition can be specially adapted to be administered in thefasted state. The terms “in the fasted state” and “under fastingconditions” are herein used interchangeably. Similarly, the terms “inthe fed state” and “under fed conditions” are herein usedinterchangeably. The composition can also be administered in either thefed or fasted state. For example, the dosage form can have a reducedfood effect. The reduced food effect can be a difference of less thanabout 35% between a AUC_(0-t) under fasting conditions and a AUC_(0-t)under fed conditions, for example a difference of less than about 33%,about 30%, about 27%, about 25%, about 23%, or about 20% between aAUC0-t under fasting conditions and a AUC_(0-t) under fed conditions. Inanother example, the composition exhibits an absorption profile underfasting conditions which is substantially similar to the absorptionprofile of a reference dosage form of itraconazole under the proprietaryname Sporanox® (the reference dosage form) under fed conditions. Inparticular, the substantial similarity is bioequivalence.

Without wishing to be bound by theory, it is believed that the use of asolid dispersion of itraconazole in an acid resistant pharmaceuticallyacceptable carrier can prevent the itraconazole from dissolving too fastin the gastric juice and subsequently precipitating out in the higher pHenvironment of the lower GI tract thereby increasing the consistency ofthe bioavailability of itraconazole.

The composition can be specially adapted to have an AUC with a reduceddose-to-dose intra-subject variability in the same subject. The reducedintra-subject variability can be with respect to the SPORANOX® dosageform. For example, the dosage form can have a reduced variability in theAUC_(0-t), C_(max), and/or T_(max) as compared to the reference dosageform, such as an intra-subject coefficient of variability under fedconditions for the AUC_(0-t) can be about 35% or less. As anotherexample an intra-subject coefficient of variability under fed conditionsfor the AUC_(0-∞) can be about 35% or less.

The composition can also comprise one or more additional antifungalagents. The one or more additional antifungal agents can comprise, forexample, amphotericin B, candicidin, filipin, hamycin, natamycin,mystatin, rimocidin, bifunazole, butoconazole, clotrimazole,fenticonazole, isoconazole, ketoconazole, miconazole, omoconazole,oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole,fluconazole, isavuconazole, itraconazole, posaconazole, ravuconazole,terconazole, voriconazole, abafungin, amorolfin, butenafine, naftifine,terbinafine, anidulafingin, casporofungin, micafungin, benzoic acid incombination with a keratolytic agent, ciclopirox, flucytosine,griseofulvin, haloprogin, polygodial, tolnaftate, undecylenic acid, zincpyrithione, selenium sulfide, piroctone olamine, tar, tea oil, andcrystal violet.

Particular parameters of the composition can be defined with respect tothe commercially available SPORANOX® itraconazole composition (the“reference composition.”) For example, when the present composition isadministered in the fed state, it can have one or more pharmacokineticparameters that are therapeutically similar to those of referencecomposition when administered in the fed state. Such therapeuticsimilarity can be determined by an in vivo pharmacokinetic study tocompare one or more pharmacokinetic parameters the two compositions. Apharmacokinetic parameter for the compositions can be measured in asingle or multiple dose study using a replicate or a nonreplicatedesign. For example, the pharmacokinetic parameters for the present oralsolid composition and for the reference composition can be measured in asingle dose pharmacokinetic study using a two-period, two-sequencecrossover design. Alternately, a four-period, replicate design crossoverstudy may also be used. Single doses of the present composition and thereference composition are administered and blood or plasma levels ofitraconazale are measured over time. Pharmacokinetic parameterscharacterizing rate and extent of itraconazole absorption are evaluatedstatistically. The area under the plasma concentration-time curve fromtime zero to the time of measurement of the last quantifiableconcentration (AUC_(0-t)) and to infinity (AUC_(0-∞)), Cmax, and Tmaxcan be determined according to standard techniques. Statistical analysisof pharmacokinetic data is performed on logarithmic transformed data(e.g., AUC_(0-t), AUC_(0-∞), or C_(nax) data) using analysis of variance(ANOVA). In one embodiment, two compositions (e.g. the presentcomposition and the reference composition) or methods (e.g., dosingunder fed versus fasted conditions) are therapeutically similar if theConfidence Interval (CI) range of 80% to 95% (e.g., including 90%)limits for a ratio of the geometric mean of logarithmic transformedAUC_(0-∞), AUC_(0-t), and/or C_(max) for the two compositions or twomethods are about 0.70 to about 1.43; or about 0.75 to about 1.33; orabout 0.80 to about 1.25.

In addition or in the alternative, the composition can betherapeutically equivalent to the reference composition. For example,administration of the composition over about the same time period as thereference composition can produce a substantially similar therapeuticoutcome.

The composition can be bioequivalent to the reference composition. Forexample, the composition can have 90% Confidence Interval (CI) limitsfor a ratio of the geometric mean of logarithmic transformed AUC_(0-∞),AUC_(0-t), and C_(max) for the composition is about 0.80 to about 1.25of the reference composition. As another example, the composition canhave 90% CI limits for a ratio of the geometric mean of logarithmictransformed AUC_(0-∞) and AUC_(0-t) of about 0.80 to about 1.25 of thereference composition.

The amount of itraconazole in the composition can be from about 50% toabout 65% by weight of the amount of itraconazole in the referencecomposition.

The composition can have an AUC_(0-t) that is about 0.70 to about 1.43of that of the reference composition. The composition can have anAUC_(0-t) that is about 0.75 to about 1.33 of that of the referencecomposition. The composition can have a relative bioavailability (Frel)of greater than about 150% relative to the reference composition underfed conditions, such as a relative bioavailability (Frel) of greaterthan about 160%, about 165%, about 170%, about 175%, or about 180%, suchas about 180%, relative to the reference composition under fedconditions.

Methods of Using Itraconazole Compositions and Dosage Forms

A method of treating a fungal infection can comprise administering oneor more dosage forms comprising itraconazole, such as one or more of thedosage forms described herein, to a subject. The subject is typically ahuman.

The fungal infection can be any infection treatable by a triazoleantifungal agent, such as itraconazole. The fungal infection can be asystemic infection or a local infection, particularly a systemicinfection. Exemplary fungal infections that can be treated include oneor more of onychomycosis, pulmonary or extrapulmonary blastomycosis,histoplasmosis, and aspergillosis. In particular, the dosage form isused to treat onychomycosis.

The dosage form can be any acceptable dosage form, such as a powder,sachet, tablet, capsule, pill, suppository, implant, wafer, cream,ointment, syrup, gel, suspension, and the like. The dosage form isparticularly an orally deliverable dosage form, such as a tablet orcapsule, and typically a capsule.

A dosage form as described herein, such as a capsule, can beadministered at appropriate intervals. For example, once per day, twiceper day, three times per day, and the like. In particular, the dosageform is administered once or twice per day. Even more particularly, thedosage form is administered once per day.

The dosage form can be administered for a duration of time sufficient totreat the fungal infection. In order to treat a fungal infection, thedosage form is typically administered for about four weeks to aboutforty weeks, particularly about eight weeks to about thirty six weeks.For example, the dosage form can be administered for about twelve weeksto about twenty four weeks. In a particular example, the dosage form isadministered for about twelve weeks, at which point the therapeuticeffect on the fungal infection is determined, for example, bydetermining the amount or degree of improvement in the patientconditions or the amount of degree of severity of the fungal infectionafter about twelve weeks of administration of the dosage form withrespect to the amount or degree of severity before administration of thedosage form. If desired, administration of the dosage form can then becontinued for about six to about thirty additional weeks, for example,about eight to about twenty eight additional weeks, such as about twelveadditional weeks. For example, the dosage form can be administered forabout twenty four weeks, which in studies was sufficient to treat mostonychomycosis infections.

One or more additional antifungal agents can be co-administered with thedosage form described herein. The one or more additional antifungalagents can comprise, for example, amphotericin B, candicidin, filipin,hamycin, natamycin, mystatin, rimocidin, bifunazole, butoconazole,clotrimazole, fenticonazole, isoconazole, ketoconazole, miconazole,omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole,albaconazole, fluconazole, isavuconazole, itraconazole, posaconazole,ravuconazole, terconazole, voriconazole, abafungin, amorolfin,butenafine, naftifine, terbinafine, anidulafingin, casporofungin,micafungin, benzoic acid in combination with a keratolytic agent,ciclopirox, flucytosine, griseofulvin, haloprogin, polygodial,tolnaftate, undecylenic acid, zinc pyrithione, selenium sulfide,piroctone olamine, tar, tea oil, and crystal violet. When administeredconcurrently, the one or more additional antifungal agents can beadministered in the same dosage form or in a different dosage form asthe itraconazole dosage forms described herein. The one or moreadditional antifungal agents can be administered at about the same timeof the day as the itraconazole dosage form described herein, or atdifferent times of the day, or even on different days. The one or moreadditional antifungal agents can also be administered by the same ordifferent route of administration as the itraconazole dosage formsdescribed herein. For example, an itraconazole dosage form describedherein can be administered orally in a capsule and an additionalantifungal agent can be administered topically as a cream.

A dosage form as described herein can be used in a method of reducingthe food effect of itraconazole. The method can comprise administering adosage form, such as a dosage form described herein, to a subject. Themethod can result in a bioavailability, as measured by AUC, in thefasted state that bears greater similarity to the bioavailability, asmeasured by AUC, in the fed state. For example, the bioavailability, asmeasured by AUC, in the fasted state can differ from that in the fedstate by about 35% or less, about 30% or less, about 25% or less, orabout 20% or less.

The dosage form used for a method of reducing food effect is typicallyan oral dosage form, such as a tablet, capsule, powder, sachet, lozenge,and the like, and particularly a capsule.

A dosage form as described herein can also be used in a method ofadministering itraconazole to a fasted subject, for example, a subjectwho has not eaten a meal about 30 minutes or more, about 1 hour or more,about 2 hours or more, about 3 hours or more, about 4 hours or more,about 5 hours or more, about 6 hours or more, about 7 hours or more,about 8 hours or more, about 9 hours or more, or about 10 hours or morebefore ingesting the dosage form.

The dosage form used for a method of administering itraconazole to afasted subject is typically an oral dosage form, such as a tablet,capsule, powder, sachet, lozenge, and the like, and particularly acapsule.

A dosage form as described herein can also be used in a method ofadministering itraconazole to a subject, wherein the subject is ineither a fed or fasted state. The dosage form used for such a method istypically an oral dosage form, such as a tablet, capsule, powder,sachet, lozenge, and the like, and particularly a capsule.

A dosage form as described herein can also be used in a methodcomprising coadministering an itraconazole dosage form with one or moresecond pharmaceutically active agents that alters the gastric pH, andparticularly drugs that increase gastric pH. The second pharmaceuticallyactive agent can be a gastric acid suppressor or neutralizer. Examplesof second pharmaceutically active agents that alter the gastric pHinclude antacids, proton pump inhibitors, and H2-receptor antagonists.Exemplary antacids include alkali or alkali earth salts of carbonate orbicarbonate, such as sodium bicarbonate, potassium bicarbonate, calciumcarbonate, magnesium carbonate, sodium carbonate, and potassiumcarbonate, hydroxides such as aluminum hydroxide and magnesiumhydroxide, and, bismuth subsalicylate. Exemplary proton pump inhibitorsinclude omeprazole, lansoprazole, dexlansoprazole, esomeprazole,pantoprazole, rabeprazole, and ilaprazole. Exemplary H2-receptorantagonists include cimetidine, ranitidine, famotidine, and nizatidine.

Without wishing to be bound by theory, it is believed that altering, andparticularly raising, the gastric pH substantially lowers thebioavailability of itraconazole in the SPORANOX® formulation. Thus,coadministration of antiacids, proton pump inhibitors, and H2-receptorantagonists is counterindicated for SPORANOX®. However, many of thedosage forms disclose herein feature a solid dispersion of itraconazoleand an acid-resistant carrier. The acid resistant carrier is believed toprotect the itraconazole from the effect of the less acidic environment.

A method of treating cancer can comprise administering a dosage formdescribed herein to a patient. The cancers that can be treated includeone or more of acute lymphoblastic leukemia, acute myeloid leukemia,adrenocortical carcinoma, kaposi sarcome, lymphoma, anal cancer,appendix cancer, central nervous system cancer, basel cell carcinoma,bile duct cancer, bladder cancer, ewing sarcoma, osteosarcoma, malignantfibrous histiocytoma, brain stel glioma, cancerous brain tumors, such asbrain stem glioma, craniopharygnioma, and ependymoma, breast cancer,broncial tumors, Burkitt lymphoma, carcinoid tumors, includinggastrointestinal carcinoid tumors, cancerous cardiac tumors, embryonaltumors, germ cell tumors, primary lymphoma, cervical cancer, chroniclymphocytic leukemia, chronic myelogenous leukemia, chronicmyeloproliferative disorders, colon cancer, colorectal cancer, cutaneousT-cell lymphoma, bile duct cancer, ductal carcinoma, endometrial cancer,ependymoma, esophageal cancer, esthesioneuroblasoma, Ewing sarcoma,extracranial germ cell tumor, extraganodal germ cell tumor, extrahepaticbile duct cancer, cancers of the eye, such as intraocular melanoma andretinoblastoma, fibrous histiocytoma of bone, gallbladder cancer,gastric cancer, gastrointestinal carcinoid tumor, gastrointestinalstroma tumors (GIST), germ cell tumors, including central nervoussystem, extracranial, extragonadal, ovarian, and testicular, gestationaltrophoblastic disease, glioma, hairy cell leukemia, head and neckcancer, heart cancer, heatocellular (liver) cancer, histiocytosis ofLangerhans cell, Hodgkin's lymphoma, hyopharyngeal cancer, islet celltumors, pancreatic neuroendocrine tumors, kidney cancers, such as renalcell cancers and Wilms tumors, Langerhans cell histiocytosis, laryngealcancer, leukemia, such as acute lymphoblasitc leukemia, acute myeloidleukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia,and hairy cell leukemia, lip and oral cavity cancers, liver cancers,lobular carcinoma in situ, lung cancers, such as non-small cell andsmall cell lung cancers, lymphomas, including AIDS-related, Burkitt,non-Hodgin, cutaneous T-cell, Hodgin, and primary central nervoussystem, Waldenstrom macroglobulinemia, male breast cancer, melanoma,Merkel cell carcinoma, malignang mesothelioma, metastatic squamous neckcancer, midline tract carcinoma, such as those involving the NUT gene,mouth cancer, multiple endocrine neoplasa syndromes, multiplemyeloma/plasma cell neoplasm, mycosis fungoides, myelodyplasticsyndromes, myelodyplasitc/myeloproliferative neoplasms, myelogenousleukemia, either chronic or acute, myeloma, myeloproliferativedisorders, nasal cavity and paranasal sinus cancer, nasopharyngealcancer, neurolastoma, oral cancer, oral cavity cancer, such as lip andoraopharyngeal cancer, ovarian cancer, such as epithelial, germ celltumor, and low malignant potential tumors of the ovaries, pancreaticcancer, such as pancreatic neuroendocrine tumors (Islet cell tumors),papillomatisis, paragangioma, paranasal sinus and nasal cavity cancer,parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma,pituitary tumors, plasma cell neoplasms, multiple myeloma,pleuropulmonary blastoma, pregnancy and breast cancer, primary centralnervious system (CNS) lmphoma, prostate cancer, rectal cancer, renalcell (kidney) cancer, renal pelvis and ureter cancers, retinoblastoma,rhabdomysarcoma, salivary gland cancer, sarcomas, such as Ewing, Kaposi,osteosarcoma, rhabdomysarcoma, soft tissue, and uterine, Seazarysyndrome, skin cancers, such as melanoma, Merkel cell carcinoma, andnonmelanoma, small cell lung cancer, small intestine cancer, soft tissuesarcoma, sqaumous cell carcinoma, stomach (gastric) cancers, cutaneousT-cell lymphoma, testicular cancer, throat cancer, thymoma and thymiccarcinomas, thyroid cancer, transitional cell cancer of the renal pelvisand ureter, carcinomas of unknown primary origin, unusual cancers ofchildhood, urethral cancer, uterine cancer, uterine sarcoma, vaginalcancer, vulvar cancer Waldenstrom macroglobuloma, and Wilms tumors.Particular cancers include prostate cancers, skin cancers, and lungcancers. Of the prostate cancers, non-metastatic castration resistantprostate cancer is particularly contemplated. Of the skin cancers,advance basal cell carcinoma (NBCCS) is particularly contemplated. Ofthe lung cancers, non-small cell lung cancer (NSCLC) and squamous celllung cancer are particularly contemplated.

Methods of treating any of the above-mentioned cancers can includeadministering an appropriate amount number of dosages of a formdescribed herein, the dosage forms having a sufficient amount ofitraconazole to treat the cancer of interest. The dosage form can beadministered once a day, twice a day, three times a day, four times aday, or more. Administration can take place for as long as necessary forthe cancer of interest to be treated, for example, until the cancer goesinto remission.

The dosage for treating cancer can be the same or different from theamount of itraconazole per dose used to treat fungal infections. Whendifferent, the amount of itraconazole per dose for treating cancer canbe, for example, about 100 mg or higher, such as about 200 mg or higher,about 300 mg or higher, about 400 mg or higher, about 600 mg or higher,about 700 mg or higher, about 800 mg or higher, about 900 mg or higher,or about 1,000 mg or higher. For example, the dosage can be about 100 mgto about 1,000 mg, about 200 mg to about 1,000 mg, about 200 mg to about900 mg, about 300 mg to about 900 mg, about 300 mg to about 700 mg, andthe like, such as any therapeutically effective amount of itraconazole.

EXAMPLES Formulation Examples Example 1—Formulation of 50, 60 and 70 mgLOZANOC Dosage Form

A solid dispersion was prepared by dispersing 0.6 kg of hydroxypropylmethylcellulose acetate phthalate (sold under the name HP-50) in 12.0 kgof methylene chloride and then adding 0.4 kg of itraconazole withstirring until a pale brown solution formed. The solution wasspray-dried using a dual-fluid nozzle sprayer with 70° C. air inlettemperature and 15-20° C. air outlet temperature to form the soliddispersion as a spray dried powder.

870 g of the spray dried powder was blended with 209.0 g of sodiumstarch glycolate and 9.0 g of colloidal silicon dioxide. 13.0 g ofmagnesium stearate was added to the blend, and the mixture was furtherblended until uniform.

The powder was filled into size 0 gelatin capsules in an amountsufficient to provide 50 mg, 60 mg, or 70 mg of itraconazole percapsule, which corresponds to 158 mg, 190 mg, and 221 mg of powder percapsule, respectively. The content of the powder and the capsules isprovided in Table 2.

TABLE 2 Weight Mass in Mass per percent Powder (g) Capsule (mg)Dispersion Components Itraconazole 31.61 348.0 50 60.0 70.0Hydroxypropyl 47.41 522.0 75 90.0 105.0 methylcellulose phthalate Othercomponents Sodium starch 18.98 209.0 30.0 36.0 42.0 glycolate Silicondioxide 0.82 9.0 1.25 1.50 1.75 Magnesium 1.18 13.0 1.85 2.22 2.59stearate Total 100 1101.0 158.1 189.7 221.3

Example 2—Formulation of 50 mg LOZANOC Dosage Form

A solid dispersion was prepared by dispersing 11.4 kg of hydroxypropylmethylcellulose acetate phthalate (sold under the name HP-50) in 228 kgof methylene chloride and then adding 7.6 kg of itraconazole withstirring until a pale brown solution formed. The solution wasspray-dried using a dual-fluid nozzle sprayer with 70° C. air inlettemperature and 15-20° C. air outlet temperature to form the soliddispersion as a spray dried powder.

16.998 kg of the spray dried powder was blended with 4.081 kg of sodiumstarch glycolate and 0.17 kg of colloidal silicon dioxide. 0.252 kg ofmagnesium stearate was added to the blend, and the mixture was furtherblended until uniform.

The powder was filled into size 1 gelatin capsules in an amountsufficient to provide 50 mg of itraconazole per capsule. The content ofthe powder and the capsules is provided in Table 3.

TABLE 3 Weight Mass in Mass per percent Powder (kg) Capsule (mg)Dispersion Components Itraconazole 31.62 6.799 50 Hydroxypropyl 47.4410.199 75 methylcellulose phthalate Other components Sodium starch 18.984.801 30.0 glycolate Silicon dioxide 0.79 0.170 1.25 Magnesium 1.170.252 1.85 stearate Total 100 21.501 158.1

Example 3—Formulation of 65 mg LOZANOC Dosage Form

A solid dispersion was prepared by dispersing 13.50 kg of hydroxypropylmethylcellulose acetate phthalate (sold under the name HP-50) in 270 kgof methylene chloride and then adding 9.0 kg of itraconazole withstirring until a pale brown solution formed. The solution wasspray-dried using a dual-fluid nozzle sprayer with 70° C. air inlettemperature and 15-20° C. air outlet temperature to form the soliddispersion as a spray dried powder.

22.014 kg of the spray dried powder was blended with 5.284 kg of sodiumstarch glycolate and 0.219 kg of colloidal silicon dioxide. 0.326 kg ofmagnesium stearate was added to the blend, and the mixture was furtherblended until uniform.

The powder was filled into size 1 gelatin capsules in an amountsufficient to provide 65 mg of itraconazole per capsule. The content ofthe powder and the capsules is provided in Table 4.

TABLE 4 Weight Mass in Mass per percent Powder (kg) Capsule (mg)Dispersion Components Itraconazole 31.62 8.806 65 Hydroxypropyl 47.4413.208 97.5 methylcellulose phthalate Other components Sodium starch18.98 5.284 39.0 glycolate Silicon dioxide 0.79 0.219 1.63 Magnesium1.17 0.326 2.41 stearate Total 100 27.843 205.5

Clinical Examples

Background and Introduction

Itraconazole is a poorly water-soluble drug and exhibits lowbioavailability (Fz50%) from the current SPORANOX® 100 mg Capsules.Clinical use demonstrates relatively poor absorption associated withsignificant inter-patient variability and a highly variable effect offood on bioavailability of the drug. Formulation improvements couldovercome the poor solubility of itraconazole in water and enhance itsbioavailability.

The data below describes studies for the development of a newformulation of itraconazole (alternatively described in the studies as“itraconazole test formulation”, SUBA-itraconazole,SUBACAP™-itraconazole, or LOZANOC).

The Applicant has developed a 50 mg itraconazole capsule formulation,LOZANOC 50 mg Hard Capsules, which with 1×50 mg capsule provides plasmalevels comparable to those following administration of 1×SPORANOX® 100mg Capsules. Applicants are also developing a 65 mg dosage of LOZANOC.

LOZANOC 50 mg Hard Capsules are powder-filled capsules consisting of ablend of itraconazole spray-dried powder and capsule blend excipients,encapsulated into hard gelatin Size #1, light blue, opaque gelatincapsules (Example 1). All inactive ingredients in LOZANOC 50 mg HardCapsules formulation are present in concentrations at or below thelevels that have been previously approved for orally administeredproducts.

LOZANOC 50 mg Hard Capsules is a change in strength of the activesubstance vis-à-vis the reference medicinal product, SPORANOX® 100 mgCapsules, with no other changes, including in drug substance,pharmaceutical form, therapeutic indications, or route ofadministration.

Bioavailability Studies Example 4—Comparison of the RelativeBioavailability of LOZANOC 50 mg Capsules with SPORANOX® (Itraconazole)100 mg Capsules Under Fed Conditions

Study Rationale

One bioavailability study investigated the comparative bioavailabilityof the test itraconazole capsule (LOZANOC at doses of 50, 60 and 70 mg,with the reference formulation, SPORANOX® 100 mg capsule. In a previousstudy conducted at CMAX to investigate the bioequivalence of the testitraconazole formulation as a 100 mg capsule with the referenceformulation, SPORANOX® 100 mg capsule, the test formulation was found tobe superbioavailable, with least square mean ratio from analysis oflogarithmically transformed data of 286% for itraconazole and 303% forhydroxyitraconazole. In a further study to compare test itraconazoleformulation as a 100 mg capsule with the reference formulation,2×SPORANOX® 100 mg capsule, the comparative bioavailability was 80% foritraconazole and 85% for hydroxyitraconazole. The current study wasplanned to investigate the pharmacokinetics of a range of dose levelsfor the test formulation to determine a dose level with comparativebioavailability similar to SPORANOX® 100 mg capsule.

Study Design

A single-dose, randomized, balanced, open-label, four treatment,four-way crossover study. Twelve subjects were studied. All subjectsparticipated in the four treatment periods. Each subject received foursingle oral doses of itraconazole, at dose levels of 50 mg, 60 mg, and70 mg of the test itraconazole formulation, and a dose level of 100 mgdose of SPORANOX®, Itraconazole reference formulation, according to thetreatment randomization schedule. Each subject received the doses afterconsuming a standardized high fat breakfast. The interval between dosingoccasions was at least 7 days, which was considered adequate to preventcarryover of itraconazole between treatment periods.

Study Population

Twelve healthy male subjects, aged between 18 to 50 years, who fulfilledthe entry criteria, participated in this study.

Study Treatments

Study Drug: Itraconazole capsules, 50, 60 and 70 mg. Subjects wereadministered either Treatment B (1×50 mg LOZANOC itraconazole capsule),Treatment C (1×60 mg LOZANOC itraconazole capsule), or Treatment D (1×70mg LOZANOC itraconazole capsule). The doses were administered within 30minutes of consumption of a standardized high (50%) fat breakfast.

Reference Drug: SPORANOX®, Itraconazole capsules, 100 mg. Subjects wereadministered with Reference Formulation 1 (1×100 mg SPORANOX®,Itraconazole capsules) within 30 minutes of consumption of astandardized high (50%) fat breakfast.

A single oral dose was administered in each treatment period with 240 mLof room temperature water following a standardized high fat (50%) meal.Each subject received one of four possible treatments in each studyperiod according to the treatment randomization schedule. A single dosewas administered in each treatment period in the fed state, with aminimum of 7 days between doses.

Blood samples for pharmacokinetic analysis were collected at 1.0, 2.0,3.0, 4.0, 5.0, 6.0, 8.0, 10, 12, 24, 36, and 48 hours after dosing.Pre-dose samples were collected up to 60 minutes prior to dosing. Theblood samples were centrifuged at approximately 2500 rpm for 15 minutes,and the plasma collected for evaluation. Plasma samples were analyzedfor itraconazole and 2-hydroxyitraconazole concentrations and agentpharmacokinetics.

The pharmacokinetic sampling schedule was based on results of previousstudies and published results indicating an elimination half-life in therange of 13 to 24 hours, and peak plasma concentration at 5 to 10 hourspost-dose for dose administration under fed conditions.

Pharmacokinetic Analysis

The concentration of itraconazole and hydroxyitraconazole (a metaboliteof itraconazole) were measured in plasma samples from all subjects,using a validated assay method. Concentrations below quantization wereassigned a value of zero. The concentration-time profiles for eachsubject and the mean concentration-time profiles were plotted withlinear and logarithmic axes for concentration. The plasma concentrationsat all time points were determined. The major pharmacokinetic parametersof itraconazole and hydroxyitraconazole calculated were:

1) maximal concentration (Cmax);

2) time to maximal concentration (Tmax);

3) area under the concentration-time curve from Time zero to the lastmeasurable concentration after dosing (AUCt), calculated using thelinear trapezoidal rule;

4) apparent terminal elimination rate, calculated as the slope of theregression line for the terminal log-linear plasma concentration-timevalues, using a minimum of 3 data points (using 4 or 5 data points whereappropriate);

5) terminal elimination half-life (Thalf), calculated as 0.693/Kel,where 0.693=ln(2);

6) area under the concentration-time curve from 0 to infinity (AUCinf),calculated as AUCt+Clast/Kel where Clast is the last measurableconcentration; and

7) percent extrapolated AUCt, calculated as (AUCinf−AUCt)/AUCinf.

Comparative Bioavailability Analysis

A parametric (normal-theory) general linear model was applied to each ofthe above variables using SAS® (Version 8.2). In addition, thelogarithmic transformation of AUCt, AUCinf and Cmax, were analyzed withthe same model. The analysis of variance (ANOVA) model included thefollowing factors: sequences, subjects within sequence, period andformulation. Comparative bioavailability was assessed for thelog-transformed parameters AUCt, AUCinf and Cmax by constructing 90%confidence intervals for the ratio of the test and reference means. The90% confidence interval was obtained from the antilogs of the lower andupper bounds of the 90% confidence interval for the difference in themeans of the log-transformed data. Mean ratio values, intrasubject CV %and intersubject CV % values, were provided for log-transformed values.Treatments being compared would be deemed to have comparablebioavailability if the 90% confidence interval of the ratios of the testand reference means for log transformed AUCt and Cmax fell within theacceptance interval of 80% to 125%, in accordance with the FDA Guidancefor Industry: Guidance for Industry: Bioavailability and BioavailabilityStudies for Orally Administered Drug Products—General Considerations(Revision 1, March 2003)

The pharmacokinetic parameters and observations were compared betweentreatments for all subjects who completed the study.

Statistical and Analytical Methods

Pharmacokinetic parameters were determined using calculation softwaredeveloped specifically for CMAX (Area Under Curve, Version 3.0.1).Statistical analysis was performed using SAS® (Version 8.2).Logarithmically transformed AUCt, AUCinf and Cmax for itraconazole andhydroxyitraconazole were analyzed using an ANOVA model with termsincluding sequences, subjects within sequence, period and formulation.The residual mean squares were used to calculate the 90% confidenceinterval for the differences between formulation means. These werebacktransformed to give the confidence intervals for the mean ratios.Observed values of Kel and Thalf were also analyzed using this ANOVAmodel.

Missing and Aberrant Values

There were no missing values for itraconazole and hydroxyitraconazoleconcentration. Values reported as below quantization were considered aszero in calculating summaries of concentrations by treatment over time.Concentrations for Subjects 011 and 012 at Hour 10 in Period 3 wereaberrant compared with adjacent values. It was considered a possibilitythat these samples may have been mislabeled, swapped between thesesubjects. However, this could not be confirmed from the documentation.The pharmacokinetic analysis was performed with the values as reported.

Pharmacokinetic Results

FIGS. 1 (linear) and 2 (semi-logarithmic) show the plasma itraconazoleconcentration against time. FIGS. 3 (linear) and 4 (semi-logarithmic)show the plasma hydroxyitraconazole concentration against time.

Table 5 shows the summary of the pharmacokinetic parameters ofitraconazole and hydroxyitraconazole for each treatment for the twelvesubjects.

TABLE 5 Summary of pharmacokinetics of itraconazole andhydroxyitraconazole Reference Formulation A: Test Formulation B: TestFormulation C: Test Formulation D: Mean 100 mg Sporanox ® 50 mgItraconazole 60 mg Itraconazole 70 mg Itraconazole (Standard Deviation)capsule capsule capsule capsule Itraconazole Cmax 46.1 (27.7) 54.4(19.6) 65.9 (30.1) 77.9 (30.2) (ng/mL) AUCt 505.5 (326.8) 511.8 (206.8)671.8 (275.2) 845.2 (327.0) (ng*h/mL) AUCinf 658.4 (374.2) 579.9 (197.0)811.8 (367.4) 1044.9 (351.6) (ng*h/mL) Hydroxy- Cmax 89.4 (46.6) 98.2(28.6) 106.1 (22.7) 128.6 (27.1) itraconazole (ng/mL) AUCt 1118.4(720.7) 1169.1 (455.7) 1522.6 (626.6) 1973.3 (772.7) (ng*h/mL) AUCinf1196.7 (755.5) 1286.1 (476.1) 1598.0 (639.0) 2047.4 (797.1) (ng*h/mL)

The comparative bioavailability of each strength of the test formulationcompared with the reference treatment, was determined in the usualmanner for bioequivalence assessment, as the 90% confidence interval ofthe ratio of least squares means from analysis of variance oflog-transformed Cmax, AUCt and AUCinf. Table 6 shows the comparativebioavailability of each strength of the test formulation compared withthe reference treatment, determined as the ratios of at least squaresmeans from analysis of variance of log-transformed data.

TABLE 6 Comparative bioavailability of itraconazole andhydroxyitraconazole Test Formulation B: Test Formulation C: TestFormulation D: 50 mg Itraconazole 60 mg Itraconazole 70 mg ItraconazoleLeast Squares capsule vs capsule vs capsule vs Mean Ratio ReferenceFormulation A: Reference Formulation A: Reference Formulation A: (90%Confidence 100 mg Sporanox ® 100 mg Sporanox ® 100 mg Sporanox ®Interval) capsule capsule capsule Itraconazole Cmax 124.6%(98.8%-157.0%) 146.5% (116.3%-184.6%) 177.7% (141.1%-223.9%) AUCt 113.2%(93.4%-137.1%) 149.9% (123.7%-181.6%) 189.6% (156.5%-229.8%) AUCinf107.1% (88.3%-130.0%) 132.5% (110.4%-159.1%) 176.9% (148.0%-211.5%)Hydroxy- Cmax 117.4% (99.1%-139.2%) 129.3% (109.1%-153.3%) 156.6%(132.2%-185.6%) itraconazole AUCt 119.3% (97.2%-146.3%) 154.3%(125.8%-189.3%) 200.2% (163.2%-245.6%) AUCinf 117.1% (95.5%-143.7%)150.5% (123.2%-183.7%) 192.5% (157.7%-235.1%)

The mean ratios of Cmax, AUCt and AUCinf back-transformed followinganalysis on log-transformed parameters, for the test 50 mg, 60 mg and 70mg itraconazole capsules compared with the reference 100 mg SPORANOX®were all greater than 100%. The 90% confidence interval for the leastsquares itraconazole and hydroxyitraconazole mean ratio of AUCt, Cmaxand AUCinf, log-transformed data, extended above the standardbioequivalence acceptance interval of 80.0%-125.0% for the test 50 mg,60 mg and 70 mg itraconazole capsules compared with the reference 100 mgSPORANOX®.

Safety and Tolerability

A total of 25 adverse events were reported by 9 of the 12 (75%) subjectsduring the conduct of the study. There were no deaths or other seriousadverse events reported. Five of the adverse events, experienced for5/12 subjects (42%), were deemed to be possibly related to the studytreatments. Of these, 2 adverse events were experienced by 2 of 12 (17%)subjects after receiving the test formulation 50 mg itraconazolecapsule, 1 adverse event was experienced by 1 of 12 (8%) subjects afterreceiving the test formulation 70 mg itraconazole capsule, and 2 adverseevents were experienced by 2 of 12 (17%) subjects after receiving thereference formulation 100 mg SPORANOX® capsule. No adverse eventsexperienced by subjects receiving the test formulation 60 mgitraconazole capsule were deemed to be possibly related to studytreatment. There were no clinically significant changes in physicalfindings or clinical laboratory results throughout the study that wereconsidered due to any study treatment, from Screening through to theExit Evaluation.

In this single oral dose, open-label, randomized, balanced, four-periodcrossover study in 12 healthy adult male subjects, the mean ratios ofCmax, AUCt and AUCinf log-transformed data for itraconazole andhydroxyitraconazole for the test itraconazole 50 mg, 60 mg and 70 mgcapsules compared with the reference SPORANOX® 100 mg were all greaterthan 100%. For test itraconazole 50 mg capsules compared with thereference SPORANOX® 100 mg, the mean ratios of Cmax, AUCt and AUCinfwere 124.6%, 113.2% and 107.1% for itraconazole and 117.4%, 119.3%, and117.1% for hydroxyitraconazole, respectively. The mean ratios of theseparameters were all greater than 125% for test itraconazole 60 mg and 70mg capsules compared with the reference SPORANOX® 100 mg. The 90%confidence intervals for the mean ratios of these parameters at all doselevels of the test formulation extended above the standardbioequivalence acceptance interval of 80.0%-125.0%.

The test 50 mg, 60 mg and 70 mg itraconazole capsules all demonstratedsuprabioavailability for itraconazole and hydroxyitraconazole comparedwith the reference 100 mg SPORANOX® capsules, given under fedconditions.

Adverse events were experienced by 2/12 subjects (17%) followingadministration of the reference formulation, and by 4/12 (33%), 5/12(42%), and 3/12 (25%) following administration of the test formulationat strengths of 50 mg, 60 mg, and 70 mg, respectively. There were nodeaths or other serious adverse events during the study. No adverseevents deemed to be possibly related were experienced by subjectsreceiving the test formulation 60 mg itraconazole. None of the subjectswithdrew from the study due to adverse events deemed related to studytreatments.

Example 5—Comparison of the Relative Bioavailability of 110 mg LOZANOCItraconazole with 200 mg SPORANOX® (Itraconazole) Under Fed and FastedConditions

Study Rationale

This study investigated the comparative bioavailability of the testitraconazole capsule (LOZANOC) at a dose of 110 mg, with 200 mg of thereference formulation, SPORANOX®. An absolute oral bioavailability ofapproximately 55% has been reported for a 100 mg dose of itraconazoleoral solution. A non-linear kinetic relationship has been found withincreasing doses of itraconazole capsules and pharmacokinetic studiessuggest that itraconazole may undergo saturation metabolism withmultiple dosing. The major metabolite, hydroxyitraconazole, hasantifungal activities similar to the parent compound. Approximately3-18% of itraconazole is excreted unchanged in the feces, and nounchanged drug is found in the urine within 24 hours following theadministration of an oral dose. The elimination half life after a singleoral dose of 50 mg to 200 mg of itraconazole in healthy subjects isreported to range between 13 hours and 24 hours. The elimination halflife of hydroxyitraconazole is reported to be 11.5 hours after a 200 mgdose of itraconazole. The oral bioavailability of itraconazole ismaximized when taken with a light meal however, there is markedintersubject variability. If itraconazole is administered in the fastingstate, peak plasma concentration (Cmax) and area under the curve (AUC)are reduced by 50-70% when compared to administration after a lightmeal.

In a previous study, the Cmax for SPORANOX® occurred at 3.6 hours. In aprevious study conducted to investigate the bioequivalence of the testitraconazole formulation as a 100 mg capsule with the referenceformulation, SPORANOX® 100 mg capsule, the test formulation was found tobe superbioavailable, with least square mean ratio from analysis oflogarithmically transformed data of 286% for itraconazole and 303% forhydroxyitraconazole. In a further study to compare test itraconazoleformulation as a 100 mg capsule with the reference formulation,2×Sporanox® 100 mg capsule, the comparative bioavailability was 80% foritraconazole and 85% for hydroxyitraconazole. The current study wasplanned to investigate the pharmacokinetics of the test formulation at adose level of 110 mg (1×50 mg capsule plus 1×60 mg capsule) under bothfed and fasted conditions to determine if a food effect is evident incomparison to SPORANOX® (2×100 mg capsules).

Study Design

A single-dose, randomized, balanced, open-label, four treatment,four-way crossover study. Twelve subjects were studied. All subjectsparticipated in the four treatment periods. Overall each subjectreceived four single oral doses of itraconazole, twice as the testformulation (110 mg as 50 mg and 60 mg capsules) under both fed andfasted conditions, and twice as the reference formulation SPORANOX®(2×100 mg capsules) under both fed and fasted conditions according tothe treatment randomization schedule. Under the fed conditions, subjectsreceived the dose after consuming a standardized high (50%) fatbreakfast. The interval between dosing occasions was at least 7 days,which was considered adequate to prevent carryover of itraconazolebetween treatment periods.

Study Population

Twelve healthy male subjects, aged between 18 to 50 years, who fulfilledthe entry criteria, participated in this study. Eleven subjectscompleted the study.

Study Treatments

Study Drug: Itraconazole capsules, 110 mg total dose administered as1×50 mg capsule and 1×60 mg capsule. Subjects received either TreatmentC (1×50 mg capsule plus 1×60 mg capsule of itraconazole test formulationadministered within 30 minutes of consumption of a standardized high fatbreakfast), or Treatment D (1×50 mg capsule plus 1×60 mg capsule ofitraconazole test formulation administered following at least a 10-hourovernight fast).

Reference Drug: SPORANOX®, Itraconazole capsules, 2×100 mg capsules.Subjects received either Treatment A (2×100 mg SPORANOX®, Itraconazolecapsules administered within 30 minutes of consumption of a standardizedhigh fat breakfast), or Treatment B (2×100 mg SPORANOX®, Itraconazolecapsules administered following at least a 10-hour overnight fast).

A single oral dose was administered in each treatment period with 240 mLof room temperature water following a standardized high fat (50%) mealor following a fast of at least 10 hours. Each subject received one offour possible treatments in each study period according to the treatmentrandomization schedule. A single dose was administered in each treatmentperiod, with a minimum of 7 days between doses.

Blood samples for pharmacokinetic analysis were collected at 1.0, 2.0,3.0, 4.0, 5.0, 6.0, 8.0, 10, 12, 24, 36, and 48 hours after dosing.Pre-dose samples were collected up to 60 minutes prior to dosing. Theblood samples were centrifuged at approximately 2500 rpm for 15 minutes,and the plasma collected for evaluation. Plasma samples were analyzedfor itraconazole and 2-hydroxyitraconazole concentrations and agentpharmacokinetics.

The pharmacokinetic sampling schedule was based on results of previousstudies and published results indicating an elimination half-life in therange of 13 to 24 hours, and peak plasma concentration at 5 to 10 hourspost-dose for dose administration under fed conditions and more rapidabsorption for dose administration under fasted conditions.

Pharmacokinetic Analysis

The pharmacokinetic analysis was performed as described in Example 4.The concentration of itraconazole and hydroxyitraconazole (a metaboliteof itraconazole) were measured in plasma samples from all subjects,using a validated assay method. Statistical and Analytical Methods wereperformed as described in Example 4.

Missing and Aberrant Values

There were no missing values for itraconazole and hydroxyitraconazoleconcentration. Values reported as below quantization were considered aszero in calculating summaries of concentrations by treatment over time.

Pharmacokinetic Results

FIGS. 5 (linear) and 6 (semi-logarithmic) show the plasma itraconazoleconcentration against time. FIGS. 7 (linear) and 8 (semi-logarithmic)show the plasma hydroxyitraconazole concentration against time.

Table 7 shows the summary of the pharmacokinetic parameters ofitraconazole and hydroxyitraconazole for each treatment for the elevensubjects.

TABLE 7 Summary of pharmacokinetics of itraconazole andhydroxyitraconazole Treatment A Treatment B Test treatment Testtreatment 200 mg Sporanox ® 200 mg Sporanox ® 110 mg itraconazole 110 mgitraconazole Mean capsule (fed) capsule (fasted) capsule (fed) capsule(fasted) (Standard Deviation) n = 11 n = 11 n = 11 n = 11 ItraconazoleCmax 230.4 (93.6) 289.9 (215.3) 225.3 (144.6) 364.6 (215.4) (ng/mL) AUCt2384.0 (1114.4) 2906.7 (1677.6) 2658.0 (1197.0) 2793.2 (1352.2)(ng*h/mL) AUCinf 2509.7 (1111.7) 3331.4 (2399.2) 3163.6 (1461.7) 2439.9(1332.1) (ng*h/mL) Hydroxy- Cmax 265.9 (109.2) 308.4 (83.3) 258.4 (77.5)335.9 (110.7) itraconazole (ng/mL) AUCt 5154.0 (2565.2) 5816.7 (2710.4)5396.4 (2192.3) 6034.1 (2753.9) (ng*h/mL) AUCinf 5654.8 (3294.2) 6629.3(3458.2) 5928.3 (2691.9) 6916.9 (3796.3) (ng*h/mL)

The comparative bioavailability of the test formulation compared withthe reference formulation (fed and fasted), and between fed and fastedadministration of the test formulation, was determined in the usualmanner for bioequivalence assessment, as the 90% confidence interval ofthe ratio of least squares means from analysis of variance oflog-transformed Cmax, AUCt and AUCinf. Table 8 shows the comparativebioavailability of the test formulation compared with the referencetreatment under fed and fasted conditions, determined as the ratios ofat least squares means from analysis of variance of log-transformeddata.

TABLE 8 Comparative bioavailability of itraconazole andhydroxyitraconazole Treatment C: Treatment D: Treatment C: Least Squares110 mg itraconazole 110 mg itraconazole 110 mg itraconazole Mean Ratiotest capsule (fed) test capsule (fasted) test capsule (fed) (90%Confidence vs Treatment A: vs Treatment B: vs Treatment D: Interval) 200mg Sporanox ® 200 mg Sporanox ® 110 mg itraconazole n = 11 capsule (fed)capsule (fasted) test capsule (fasted) Itraconazole Cmax 89.1%(67.1%-118.3%) 122.0% (91.9%-162.0%) 64.2% (48.4%-85.3%) AUCt 103.0%(84.5%-125.6%) 94.0% (77.1%-114.7%) 97.4% (79.9%-118.7%) AUCinf 111.2%(86.8%-142.4%) 82.0% (61.3%-109.7%) 111.6% (84.5%-147.4%) Hydroxy- Cmax97.8% (81.4%-117.7%) 105.7% (87.9%-127.1%) 77.9% (64.7%-93.6%)itraconazole AUCt 101.8% (80.9%-128.0%) 98.6% (78.4%-124.0%) 92.5%(73.6%-116.4%) AUCinf 102.6% (81.7%-128.9%) 98.2% (78.2%-123.3%) 90.4%(72.0%-113.6%)

For the fed comparison between the test 110 mg itraconazole capsulescompared with the reference 200 mg SPORANOX®, Cmax of itraconazole waslower for the test formulation (LSMean=89.1%, 90% CI=67.1%-118.3%).However, for the fasted comparison between the test 110 mg itraconazolecapsules compared with the reference 200 mg SPORANOX®, Cmax ofitraconazole was higher for the test formulation (LSMean=122.0%, 90%CI=91.9%-162.0%). Comparisons of AUC parameters did not follow thistrend.

For the comparison between fed and fasted administration of the testitraconazole, Cmax was considerably lower for fed administration, withmean ratios of 64.2% for itraconazole and 77.9% for hydroxyitraconazole.The mean ratios of AUCt were more similar between fasted and fedtreatments, with mean ratios of 97.4% for itraconazole and 92.5% forhydroxyitraconazole.

A total of 12 adverse events (AEs) were reported by 5 of the 12 subjects(42%) during the conduct of the study. Most adverse events were mild inintensity, with 3 AEs of moderate severity and one AE of severeintensity (bacterial lower respiratory tract infection, deemed notrelated to study treatment). There were no AEs deemed to be probably ordefinitely related to the treatment. There were two AEs deemed by thePrincipal Investigator to be possibly related to the study treatmentexperienced by 1/12 subjects (8%), being diarrhea and headache afterreceiving the reference formulation 200 mg SPORANOX® under fed andfasted conditions, respectively. There were no deaths or other seriousadverse events during the study. None of the subjects withdrew from thestudy due to adverse events deemed related to study treatments.

Example 6—Comparison of the Relative Bioavailability of Two LOZANOC 50mg Capsules with Two SPORANOX® (Itraconazole) 100 mg Capsules TakenDaily Under Fed Conditions

Study Rationale

This study evaluated the relative bioavailability in healthy volunteersunder fed conditions of two LOZANOC 50 mg capsules with that of twoSPORANOX® (itraconazole) 100 mg capsules. Subjects were given 100 mgdoses of LOZANOC or 200 mg doses of SPORANOX® (itraconazole) under fedconditions. The pharmacokinetics of both LOZANOC and SPORANOX®(itraconazole) were compared.

Twenty-four (24) volunteers were enrolled in a randomized, multi-dose,four-treatment, four-way crossover study conducted to compare therelative bioavailability of a 100 mg dose of LOZANOC given as 2×50 mgcapsules compared to a 200 mg dose of SPORANOX® (itraconazole) (2×100 mgcapsules), when administered under fed conditions. Twenty-two (22)subjects completed the study.

Blood samples were collected according to the following schedule:

Day 1—pre-dose (0) collected up to 60 minutes prior dosing and beforebreakfast

Day 13—immediately (within 5 minutes) prior to dosing

Day 14—immediately (within 5 minutes) prior to dosing

Day 15—pre-dose (0 immediately prior to dosing, within 5 minutes), andat 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 8.0, 10, 12, 24, 36, 48,and 72 hours post dosing.

The blood samples were centrifuged at approximately 2500 rpm for 15minutes, and the plasma collected. The plasma concentration ofitraconazole and 2-hydroxyitraconazole (a metabolite of itraconazole)were measured by fully validated analytical procedures. Statisticalanalysis was performed to evaluate the relative bioavailability for theTest product compared to that of the Reference product after dailyadministration following a high fat, high calorie meal. The single-dosepharmacokinetics of each product was analyzed to identify the doseranging characteristics of each formulation. Plasma samples wereanalyzed for itraconazole and 2-hydroxyitraconazole concentrations.

Study Design

In each period, subjects were given either:

Test A: Two doses of 50 mg (2×50 mg capsule LOZANOC; Reference C: Twodoses of 100 mg (2×100 mg capsule) SPORANOX® (itraconazole).

In each dosing period, a single dose of 100 mg (2×50 mg capsules)LOZANOC or 200 mg (2×100 mg capsules) SPORANOX® (itraconazole) wasadministered to all subjects once a day for 15 consecutive days. Eachdose was given following a high fat, high calorie breakfast preceded byan overnight fast of at least 10 hours. The test formulation was LOZANOC50 mg capsules and the reference formulation was SPORANOX®(itraconazole) 100 mg capsules. The subjects received the test productin one of the study periods and the reference product in the other studyperiod; the order of administration was according to the two-treatment,two-sequence dosing randomization schedule. The interval between Day 1in each study period was 28 days.

Twenty-four (24) subjects were dosed (12 Test A, 12 Test B) in Period Iand 22 subjects were dosed (10 Test A, 12 Test B) in Period II. Subjectswere dosed once a day for 15 consecutive days in each study period.

The subjects were monitored throughout the study for any adverse events.No serious adverse events were reported.

Pharmacokinetic Analysis

Concentrations and pharmacokinetics of itraconazole andhydroxyitraconazole in plasma were determined using fully validatedanalytical methods. The Statistical Analysis System (SAS, Version 9.1.3or later) was used for all pharmacokinetic and statistical calculations.Linear and semi-logarithmic graphs of the concentration-time profilesfor each subject were provided, using the actual times of samplecollections. Graphical presentations of mean results use the scheduledtimes of sample collections. Concentration values reported for eachcollected sample are provided.

Data from subjects with missing concentration values (missed blooddraws, lost samples, samples unable to be quantified) was used if thepharmacokinetic parameters could be estimated using remaining datapoints, otherwise data from these subjects was excluded from the finalanalysis.

For all treatments the peak exposure (Cmax) is the observed maximumplasma concentration; the time to peak exposure (Tmax) is the collectiontime at which Cmax is first observed.

Areas under the curve from time zero to the last measurableconcentration (AUCt) were calculated by the linear trapezoidal method.No concentration estimates were provided for missing sample values. Anysample with a missing value was treated as if the sample had not beenscheduled for collection. Area under the curve from time zero to timeinfinity (AUCinf) was calculated as follows:(AUC_(inf))=(AUCt)+Ct/Kel,

where Ct is the last measurable drug concentration and Kel is theelimination rate constant.

The apparent first-order elimination rate constant (Kel) was estimated,when possible, from the slope of the regression line for the terminalln-linear concentration-time values. The values included in theregression lines were selected by examination of each subject'ssemi-logarithmic concentration-time plot.

The terminal half-life (Thalf) was estimated as ln(2)/Kel.

If a subject had pre-dose (0 hour sample) plasma levels greater than 5%of their measured Cmax value, all of their data for that analyte wasexcluded from the statistical analysis for that specific period. If theyhad measurable levels equal to or less than 5% of their measured Cmax,their data was included in the analysis without adjustment.

Analysis of Variance was performed using the General Linear Model (GLM)procedure of SAS, with hypothesis testing for treatment effects atα=0.05. The statistical model contains main effects of sequence, subjectwithin sequence, treatment, and period. Sequence effects were testedagainst the Type III mean square term for subjects within sequence.

All other main effects were tested against the mean square error term.Least square means for the treatments (LSMEANS statement), thedifferences between adjusted treatment means, and the standard errorsassociated with these differences (ESTIMATE statement) were calculated.

Confidence intervals (90%) for the comparison of test and reference areaand peak results were constructed to test two, one-sided hypotheses atthe α=0.05 level of significance for AUCt, AUCinf, and Cmax. Theconfidence intervals were presented for the geometric mean ratios(obtained from logarithmic transformed data).

The Cmin was measured in the plasma concentrations from the bloodsamples collected on Days 13, 14, and 15. The mean Cmin for each subjectis the mean of the observed plasma concentrations from the blood samplescollected on these days. The Cav for each subject and treatment iscalculated by finding the mean plasma concentrations over the plasmasamples collected from 0.5 through 24 hours inclusive on Day 15 (onedosing interval of the reference product).

The Degree of fluctuation (Flux) is calculated for each subject and eachtreatment using the following calculation:Flux=(Cmax following Day 15 dose−Cmin on Day 15)/Cav on Day 15.

Swing is calculated for each subject and each treatment using thefollowing calculation:Swing=(Cmax following Day 15 dose−Cmin on Day 15)/Cmin on Day 15

For calculations of the Flux and Swing, the plasma concentrationreported from the pre-dose sample on Day 15 was used.

A comparison of Test A (2×50 mg capsule LOZANOC and Reference C (2×100mg capsule) SPORANOX® (itraconazole) was computed. The meanconcentration for each study agent was also determined over the 15 daytreatment schedule.

The Confidence Intervals (90%) for the comparison of test and referencearea and peak results are constructed to test two, one-sided hypothesesat the α=0.05 level of significance as follows: on Day 15, dosing forAUC0-72, AUCinf, and Cmax. The confidence intervals are presented forthe geometric mean ratios (obtained from logarithmic transformed data).The primary determination of pharmacokinetic equivalence will be basedon the log-transformed data for itraconazole. If the 90% confidenceinterval for the test/reference ratio for Day 15 AUC0-72, AUCinf, andCmax for itraconazole fall within the range of 80.00 to 125.00%, thenequivalence has been demonstrated under steady state conditions.

The same analysis was performed on the hydroxyitraconazole data forinformational purposes.

For each serum sample, the mean concentration of the drug over time wasdetermined. The pharmacokinetic parameters were also determined for eachdrug.

FIGS. 9 (Test A) and 10 (Reference B) show the mean itraconazoleconcentration (ln-linear) versus Study Day plots for Cmin. The meanconcentration versus time plots are shown in FIGS. 11 (linear) and 12(ln-linear).

The following key pharmacokinetic parameters were evaluated: Day 15 AUCt(AUC0-72), AUCinf, Cmax, Tmax, Median Tmax, Ke, Elimhalf (T½), Cmin,Cav, Flux, and Swing. Comparative statistics (ratios and 90% confidenceinterval calculations at steady state) are presented in the tablesbelow.

Table 9 summarizes the pharmacokinetic parameters (untransformed) ofitraconazole administered daily for 15 days in a fed state.

Table 10 shows the geometric means for itraconazole based on ANOVA ofuntransformed and ln-transformed data for itraconazole Test A (2×50 mgcapsule of LOZANOC) with Reference B (2×100 mg dose of SPORANOX®(itraconazole)) after daily administration for 15 days in the fed state.

Table 11 shows the ratio of means and 90% confidence interval based onANOVA of untransformed and ln-transformed data for itraconazole Test A(2×50 mg capsule of LOZANOC) with Reference B (2×100 mg dose ofSPORANOX® (itraconazole)) after daily administration for 15 days in thefed state.

TABLE 9 Pharmacokinetic Parameters of Itraconazole Administered Daily ina Fed State Pharmacokinetic Arithmetic Mean ± SD Parameter Units Test AReference B AUCt (0-72) ng · hr/ml 13007.6748 ± 4725.2118  15845.3411 ±5743.7269  AUCinf ng · hr/ml 20144.5525 ± 13330.5217 23464.8222 ±10390.4699 Cmax ng/ml 419.0909 ± 109.7998 524.7273 ± 159.8723 Tmax hr7.8636 ± 2.7132 5.2947 ± 1.5328 Median Tmax hr 7.00 5.00 Ke 1/hr 0.0192± 0.0086 0.0186 ± 0.0092 Elimhalf hr 45.3011 ± 29.0137 48.5164 ± 33.8293Cmin Day 13 ng/ml 172.44 ± 51.96  224.40 ± 82.57  Cmin Day 14 ng/ml181.97 ± 54.23  234.63 ± 86.97  Cmin Day 15 ng/ml 186.95 ± 61.86  244.86± 97.02  Mean Cmin ng/ml 186.9500 ± 61.8644  244.8636 ± 97.0166  Cavng/ml 250.8973 ± 73.7361  334.3223 ± 99.0344  Flux — 0.9668 ± 0.41200.8518 ± 0.2991 Swing — 1.4100 ± 0.8949 1.3095 ± 0.7828

TABLE 10 Geometric Means of Itraconazole after daily administration inthe fed state Geometric Means Based on ANOVA of Untransformed andLn-Transformed Data Untransformed Data Ln-Transformed Data AUCt AUCinfCmax AUCt AUCinf Cmax (ng · hr/ml) (ng · hr/ml) (ng/ml) (ng · hr/ml) (ng· hr/ml) (ng/ml) Test A 12996.31 20346.30 415.73 12211.78 17437.69401.90 Reference B 15700.92 24874.99 519.41 14649.35 21695.30 495.74

TABLE 11 Ratio of Means and 90% Confidence Interval of Itraconazoleafter daily administration in the fed state Ratio of Means, and 90%Confidence Intervals Based on ANOVA of Untransformed and Ln-TransformedData Untransformed Data Ln-Transformed Data AUCt AUCinf Cmax AUCt AUCinfCmax (ng · hr/ml) (ng · hr/ml) (ng/ml) (ng · hr/ml) (ng · hr/ml) (ng/ml)Ratio 0.8277 0.8179 0.8004 0.8336 0.8038 0.8107 CI 0.7342-0.92130.6861-09498 0.7105-0.8902 0.7535-0.9222 0.6832-0.9456 0.7334-0.8962p-value 0.0047 0.0283 0.0010 0.0055 0.0321 0.0018

Table 12 shows the statistical summary of the comparativebioavailability data from this study.

TABLE 12 Statistical Summary of Comparative Bioavailability Data forItraconazole Drug SUBA ™ Irtraconazole Capsules Dose (Test 2 × 50 mg;Reference 2 × 100 mg) Least Squares Geometric Means, Ratio of Means, and90% Confidence Intervals Fed Bioequivalence Study (Study No. 10850705)Parameter Test Reference Ratio 90% C.I. AUC0-t* 12212 14649 0.83360.7535-0.9222 AUC∞* 17438 21695 0.8038 0.6832-0.9456 Cmax* 402 4960.8107 0.7334-0.8962

The same analyses were performed for 2-hydroxyitraconazole, a metaboliteof itraconazole. FIGS. 13 (Test A) and 14 (Reference C) show the meanconcentration (ln-linear) versus Study Day plots for Cmin for2-hydroxyitraconazole after daily administration of the itraconazoleformulations under a fed state. The mean concentration versus time plotsfor 2-hydroxyitraconazole are shown in FIGS. 15 (linear) and 16(ln-linear).

Table 13 summarizes the pharmacokinetic parameters (untransformed) of2-hydroxyitraconazole after administration of the Test and Referenceagents daily for 15 days in a fed state.

TABLE 13 Pharmacokinetic Parameters of 2-Hydroxyitraconazole afterAdministration of Itraconazole Daily in a Fed State PharmacokineticArithmetic Mean ± SD Parameter Units Test A Reference B AUCt (0-72) ng ·hr/ml 25929.8512 ± 10133.4980 31583.4798 ± 12930.4733 AUCinf ng · hr/ml34366.0362 ± 18017.8441 45893.3050 ± 28163.7792 Cmax ng/ml 613.7273 ±156.0236 740.2273 ± 243.2432 Tmax hr 8.5455 ± 2.9395 7.9530 ± 2.8695Median Tmax hr 10.00 8.00 Ke 1/hr 0.0327 ± 0.0204 0.0281 ± 0.0183Elimhalf hr 28.6001 ± 14.5803 34.7349 ± 19.8660 Cmin Day 13 ng/ml 424.27± 140.28 552.95 ± 212.59 Cmin Day 14 ng/ml 451.59 ± 129.52 549.59 ±194.02 Cmin Day 15 ng/ml 437.55 ± 136.34 560.86 ± 203.09 Mean Cmin ng/ml437.5455 ± 136.3402 560.8636 ± 203.0860 Cav ng/ml 475.4873 ± 141.2199603.1541 ± 185.5448 Flux — 0.3977 ± 0.1912 0.3164 ± 0.1938 Swing —0.4559 ± 0.2812 0.3755 ± 0.2718

Table 14 shows the geometric means based on ANOVA of untransformed andln-transformed data for 2-hydroxyitraconazole after daily administrationof itraconazole Test A (2×50 mg capsule of LOZANOC) or Reference B(2×100 mg dose of SPORANOX® (itraconazole)) for 15 days in the fedstate.

TABLE 14 Geometric Means of 2-Hydroxyitraconazole after dailyadministration of itraconazole in the fed state Geometric Means Based onANOVA of Untransformed and Ln-Transformed Data Untransformed DataLn-Transformed Data AUCt AUCinf Cmax AUCt AUCinf Cmax (ng · hr/ml) (ng ·hr/ml) (ng/ml) (ng · hr/ml) (ng · hr/ml) (ng/ml) Test A 25972.5834635.61 611.46 23932.62 29914.03 592.67 Reference B 31397.61 45873.13732.43 28533.04 37918.58 696.31

Table 15 shows the ratio of means and 90% confidence intervals based onANOVA of untransformed and ln-transformed data for 2-hydroxyitraconazoleafter daily administration of itraconazole Test A (2×50 mg capsule ofLOZANOC) or Reference B (2×100 mg dose of SPORANOX® (itraconazole)) for15 days in the fed state.

TABLE 15 Ratio of Means and 90% Confidence Interval ofHydroxyitraconazole after daily administration of itraconazole in thefed state Ratio of Means, and 90% Confidence Intervals Based on ANOVA ofUntransformed and Ln-Transformed Data Untransformed Data Ln-TransformedData AUCt AUCinf Cmax AUCt AUCinf Cmax (ng · hr/ml) (ng · hr/ml) (ng/ml)(ng · hr/ml) (ng · hr/ml) (ng/ml) Ratio 0.8272 0.7550 0.8348 0.83880.7889 0.8512 CI 0.7114-0.9430 0.5995-0.9105 0.7226-0.9471 0.7400-0.95070.6758-0.9210 0.7666-0.9450 p-value 0.0081 0.0133 0.0196 0.0252 0.01560.0151

Example 7—Comparison of the Relative Bioavailability of Two LOZANOC 50mg Capsules with Two SPORANOX® (Itraconazole) 100 mg Capsules TakenTwice Daily Under Fed Conditions

Study Rationale

This study evaluated the relative bioavailability in healthy volunteersunder fed conditions of two LOZANOC 50 mg capsules with that of twoSPORANOX® (itraconazole) 100 mg capsules. Subjects were given 100 mgdoses of LOZANOC or 200 mg doses of SPORANOX® (itraconazole) under fedconditions twice daily for 14.5 days. The pharmacokinetics of bothLOZANOC and SPORANOX® (itraconazole) were compared.

Twenty-four (24) volunteers were enrolled in this randomized,multi-dose, steady-state, two-treatment, crossover study conducted tocompare the relative bioavailability of twice-daily doses of 100 mgLOZANOC given as 2×50 mg capsules compared to 200 mg dose of SPORANOX®(itraconazole) (2×100 mg capsules), when administered under fedconditions. Twenty-one (21) subjects completed the study.

Blood samples were collected according to the following schedule:

Day 1—pre-dose (0) collected up to 60 minutes prior dosing and beforebreakfast

Day 13—immediately (within 5 minutes) prior to the morning dosing

Day 14—immediately (within 5 minutes) prior to the morning dosing

Day 15—pre-dose (0 immediately prior to dosing, within 5 minutes), andat 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 8.0, 10, 12 (prior toevening dose), 24, 36, 48, and 72 hours post dosing.

The blood samples were centrifuged at approximately 2500 rpm for 15minutes, and the plasma collected. The plasma concentration ofitraconazole and 2-hydroxyitraconazole (a metabolite of itraconazole)were measured by fully validated analytical procedures. Statisticalanalysis was performed to evaluate the relative bioavailability for theTest product compared to that of the Reference product after twice-dailyadministration following under fed conditions. The single-dosepharmacokinetics of each product was analyzed to identify the doseranging characteristics of each formulation. Plasma samples wereanalyzed for itraconazole and 2-hydroxyitraconazole concentrations.

Study Design

In each period, subjects were given either Test A or Reference C twice aday for 14.5 consecutive days. The agents tested were:

Test A: one dose of 100 mg (2×50 mg capsule LOZANOC;

Reference B: one dose of 200 mg (2×100 mg capsule) SPORANOX®(itraconazole).

In each dosing period, one dose of 100 mg (2×50 mg capsules) LOZANOC or200 mg (2×100 mg capsules) SPORANOX® (itraconazole) was administered toall subjects twice a day for 14.5 consecutive days. Each morning dose(Days 1 to 15) was given following a full breakfast preceded by anovernight fast of at least 10 hours. On the last day of dosing (Day 15)the morning dosing occurred following subjects consuming the FDAstandardized high fat, high calorie breakfast preceded by an overnightfast of at least 10 hours. Each evening dose (Days 1 to 14) was givenwithin 30 minutes of consuming a standardized full dinner. The morningand evening doses were separated by 12 hours. The test formulation wasLOZANOC 50 mg capsules and the reference formulation was SPORANOX®(itraconazole) 100 mg capsules. The subjects received the test productin one of the study periods and the reference product in the other studyperiod; the order of administration was according to the two-treatment,two-sequence dosing randomization schedule. The interval between Day 1in each study period was 28 days.

Twenty-four (24) subjects were dosed (12 Test A, 12 Reference B) inPeriod I and 21 subjects were dosed (12 Test A, 9 Reference B) in PeriodII. Subjects were dosed twice a day for 14.5 consecutive days in eachstudy period.

The subjects were monitored throughout the study for any adverse events.No serious adverse events were reported.

Pharmacokinetic Analysis

Concentrations of itraconazole and hydroxyitraconazole in plasma weredetermined at using fully validated analytical methods. A definition ofthe pharmacokinetic parameters, AUC, AUC-INF, CMAX, TMAX, KEL and THALF,which were derived from the plasma itraconazole and hydroxyitraconazoleconcentration data, and a description of the statistical tests whichwere performed to compare the treatments are provided below:

Area Under the Curve (AUC and AUC-INF): Area under the plasmaconcentration-time curve from time zero to the time of the lastmeasurable concentration (AUC), calculated by the linear trapezoidalmethod. Area under the curve from time zero to infinite time (AUC-INF),calculated from the sum of AUC plus the extrapolated area calculatedfrom CLAST′IKEL, where CLAST′ is the observed last measurable drugconcentration and TLAST is the time of the last measurableconcentration. i.e. AUC-INF=AUC+CLAST′/KEL.

Maximum Observed Plasma Concentration (CMAX): Maximum plasmaconcentration observed following dosing.

Time of Maximum Observed Plasma Concentration (TMAX): Sampling time ofthe observed CMAX, expressed as hours following dosing (obtained withoutinterpolation)

Apparent First-order Elimination Rate Constant (KEL): Calculated fromthe slope of the regression line for the terminal log-linear plasmaconcentration-time values.

Apparent Elimination Half-Life (THALF): Calculated as 0.693/KEL

Analysis of Variance (ANOVA): ANOVA was performed at an alpha level of0.05. The statistical model contained main effects of treatment,subject, period and sequence.

Confidence Intervals (90%): Confidence intervals (90%) for pair-wisepharmacokinetic comparisons were calculated by the t-test approach (two,one-sided) at an overall alpha level of 0.10 (=0.05 each side). Theintervals were computed for the least squares mean differences,expressed as a percent of the reference treatment mean in thecomparison, and mean ratios (following logarithmic transformation of thedata, using natural logarithms).

Power: Power to detect a 20% difference for each pair-wisepharmacokinetic comparison was calculated at =0.05.

Mean Ratio (%): Mean ratios (expressed as percentages) were calculatedfor log-transformed parameters where: Mean ratio (%)=100×exp (leastsquares mean test—least squares mean reference).

Intrasubject Variability: Intrasubject coefficient of variation (CV %)was calculated for log-transformed parameters as: 100×(MSResidual)o.5

Intersubject Variability: Intersubject coefficient of variation (CV %)was calculated for log-transformed parameters as: 100×«MSSubject(Seq)−MSResidual)/2)o.5.

Nominated sample collection times were used in the statistical analysis.A parametric (normaltheory) general linear model (GLM) was applied toeach of the calculated pharmacokinetic parameters and observationsderived from the plasma itraconazole and plasma hydroxyitraconazoleconcentrations using SA˜(Version 6.12) GLM Procedure. In addition, theparameters AUC, AUC-INF and CMAX were log-transformed using naturallogarithms (LAUC, LAUC-INF and LCMAX) and were analyzed with the samemodel. The analysis of variance ANOVA) model included the effects oftreatment, subject, period and sequence. Tukey's Studentized Range Testwas performed on means of plasma itraconazole and plasmahydroxyitraconazole concentrations at individual sampling times at analpha level of 0.05. Least squares means (LSMEANS) of each parameter foreach treatment were used in the statistical analysis. Power to detect a20% difference between formulations was calculated at =0.05. Ordinary90% confidence intervals, based on the t-test, were calculated. Theprocedures correspond to Schuirmann's two one-sided tests at the 5%level of significance. The two one-sided hypothesis was tested at the 5%level for the parameters by constructing 90% confidence intervals forthe ratios of the test and reference means. The 90% confidence intervalswere obtained from the antilogs of the lower and upper bounds of the 90%confidence intervals for the difference in the means of thelog-transformed data. Mean ratio values and intrasubject andintersubject variability (CV %) values were provided for thelog-transformed parameters CMAX, AUC and AUC-INF.

The statistical tests were performed comparing Treatment A withTreatment B.

Areas under the curve from time zero to the last measurableconcentration (AUC0-72) and truncated areas under the curve from timezero to the 12 hour concentration (AUC0-12) and the 24 hourconcentration (AUC0-24), were calculated by the linear trapezoidalmethod.

The Cmin was measured in the plasma concentrations from the bloodsamples collected on Days 13, 14, and 15. The mean Cmin for each subjectis the mean of the observed plasma concentrations from the blood samplescollected on these days. Regression analysis was conducted on the Cminvalues to determine that steady state was reached for both the test andreference agents.

The Cav for each subject and treatment was calculated by finding themean plasma concentrations over the plasma samples collected from 0.5through 12 hours inclusive on Day 15 (one dosing interval of thereference product).

The Degree of fluctuation (Flux) was calculated for each subject andeach treatment using the following calculation:Flux=(Cmax following Day 15 dose−Cmin on Day 15)/Cav on Day 15.

Swing was calculated for each subject and each treatment using thefollowing calculation:Swing=(Cmax following Day 15 dose−Cmin on Day 15)/Cmin on Day 15

For calculations of the Flux and Swing, the plasma concentrationreported from the pre-dose sample on Day 15 was used.

A comparison of Test A (2×50 mg capsule LOZANOC) and Reference B (2×100mg capsule) SPORANOX® (itraconazole) administered twice-daily for 14.5days under a fed state was computed. The mean concentration for eachstudy agent was also determined over the 15 day treatment schedule.

The Confidence Intervals (90%) for the comparison of test and referencearea and peak results are constructed to test two, one-sided hypothesesat the α=0.05 level of significance as follows: on Day 15, dosing forAUC0-12, AUC0-24, AUC0-72, AUCinf, and Cmax. The confidence intervalsare presented for the geometric mean ratios (obtained from logarithmictransformed data). The primary determination of pharmacokineticequivalence will be based on the log-transformed data for itraconazole.If the 90% confidence interval for the test/reference ratio for Day 15AUC0-12, AUC0-24, AUC0-72, AUCinf, and Cmax for the test agent fallswithin the range of 80.00 to 125.00%, then equivalence has beendemonstrated under steady state conditions.

The same analysis was performed on the hydroxyitraconazole data forinformational purposes.

For each serum sample, the mean concentration of the drug over time wasdetermined. The pharmacokinetic parameters were also determined for eachdrug.

FIGS. 17 (Test A) and 18 (Reference B) show the mean concentration ofitraconazole (ln-linear) versus Study Day plots for Cmin. FIGS. 19(linear) and 20 (ln-linear) show the mean concentration of itraconazoleversus time plots.

Table 16 shows the summary of pharmacokinetic parameters foritraconazole after twice-daily administration of either Test A (2×50 mgcapsule LOZANOC) or Reference B (2×100 mg capsule) SPORANOX®(itraconazole) under a fed state.

The values for Cav, Flux, and Swing were less for the LOZANOC capsulethan for SPORANOX® (itraconazole). The standard deviations for AUC,Cmax, and Cmin are less as well indicating that there was less varianceamong the test product as compared to the reference product.

Table 17 shows the geometric means and ratio of means and 90% confidenceintervals based on ANOVA of untransformed data of the itraconazole aftertwice daily administration under fed conditions of 100 mg LOZANOCcapsule or 200 mg SPORANOX® (itraconazole).

TABLE 16 Pharmacokinetic Parameters for itraconazole after twice-dailyadministration in a fed state Pharmacokinetic Arithmetic Mean ± SDParameter Units Test A Reference B AUC0-12 ng · hr/ml 10166.0156 ±2357.0887  14852.4889 ± 5507.3566  AUC0-24 ng · hr/ml 19264.9856 ±4620.6927  28041.6889 ± 10715.2182 AUC0-72 ng · hr/ml 42216.3483 ±8914.4673  67132.7800 ± 25020.7479 AUCinf ng · hr/ml 71903.1025 ±29372.9006 135997.1449 ± 63827.9360  Cmax ng/ml 1011.4000 ± 229.7383 1579.1333 ± 555.2887  Tmax hr 6.5000 ± 8.7770  5.000 ± 2.2991 MedianTmax hr 5.00 5.00 Ke 1/hr 0.0154 ± 0.0057 0.0127 ± 0.0054 Elimhalf hr54.2163 ± 30.9934 63.7492 ± 26.1447 Cmin Day 13 ng/ml 750.07 ± 191.10989.67 ± 390.95 Cmin Day 14 ng/ml 834.80 ± 216.61 1124.60 ± 391.65  CminDay 15 ng/ml 910.80 ± 219.86 1279.60 ± 520.63  Mean Cmin ng/ml 910.8000± 219.8640 1279.6000 ± 520.6287  Cav ng/ml 837.0000 ± 198.4605 1222.7613± 446.8402  Flux — 0.1213 ± 0.0733 0.2667 ± 0.2921 Swing — 0.1180 ±0.0765 0.2900 ± 0.3835

TABLE 17 Geometric Means, ratio of means, and 90% CI of itraconazoleafter twice-daily administration AUC0-12 AUC0-24 AUC0-72 Cmax (ng ·hr/ml) (ng · hr/ml) (ng · hr/ml) (ng/ml) Geometric Means Based on ANOVAof Untransformed Data Test A 10201.40 19321.32 42313.30 1016.12Reference B 14901.75 28145.89 67376.20 1576.84 Ratio of Means, and 90%Confidence Intervals Based on ANOVA of Untransformed Data Ratio 0.68460.6865 0.6280 0.6444 CI 0.5567-0.8125 0.5525-0.8204 0.4843-0.77170.5216-0.7672 p-value 0.0008 0.0012 0.0005 0.0002

Table 18 shows the geometric means and ratio of means and 90% confidenceintervals based on ANOVA of ln-transformed data of the itraconazoleafter twice daily administration under fed conditions of 100 mg LOZANOCcapsule or 200 mg SPORANOX® (itraconazole).

FIGS. 21 (Test A) and 22 (Reference B) show the mean concentration of2-hydroxyitraconazole (ln-linear) versus Study Day plots for Cmin aftertwice-daily administration of itraconazole in the 100 mg LOZANOC capsuleor 200 mg SPORANOX® (itraconazole) formulations. FIGS. 23 (linear) and24 (ln-linear) show the mean concentration of 2-hydroxyitraconazoleversus time plots after the twice-daily administration of the test andreference formulations under fed conditions.

Table 19 shows the summary of pharmacokinetic parameters for2-hydroxyitraconazole after twice-daily administration of either Test A(2×50 mg capsule LOZANOC) or Reference B (2×100 mg capsule) SPORANOX®(itraconazole) under a fed state.

TABLE 18 Geometric Means, ratio of means, and 90% CI of itraconazoleafter twice-daily administration AUC0-12 AUC0-24 AUC0-72 Cmax (ng ·hr/ml) (ng · hr/ml) (ng · hr/ml) (ng/ml) Geometric Means Based on ANOVAof Untransformed Data Test A 9965.16 18842.36 41448.45 993.26 ReferenceB 13967.48 26302.19 63076.86 1478.94 Ratio of Means, and 90% ConfidenceIntervals Based on ANOVA of LN-Transformed Data Ratio 0.7135 0.71640.6571 0.6716 CI 0.6321-0.8054 0.6327-0.8111 0.5738-0.7525 0.5948-0.7584p-value 0.0003 0.0004 0.0001 <0.0001

TABLE 19 Pharmacokinetic Parameters for 2-hydroxyitraonazole aftertwice-daily administration of itraconazole in a fed statePharmacokinetic Arithmetic Mean ± SD Parameter Units Test A Reference BAUC0-12 ng · hr/ml 20514.0750 ± 4477.1446 28111.7875 ± 6713.6147 AUC0-24ng · hr/ml 40356.6958 ± 8773.9782  56539.7875 ± 14275.8765 AUC0-72 ng ·hr/ml  97974.8975 ± 25878.4345 150740.2667 ± 44934.3294 AUCinf ng ·hr/ml  192315.6015 ± 139127.0685  362654.0343 ± 237849.5437 Cmax ng/ml1943.0000 ± 488.9204 2746.5000 ± 681.4171 Tmax hr  6.9525 ± 7.6539 6.3000 ± 7.2645 Median Tmax hr 5.00 3.50 Ke 1/hr  0.0151 ± 0.0068 0.0100 ± 0.0044 Elimhalf hr  60.9200 ± 44.1098  86.2167 ± 46.1494 CminDay 13 ng/ml 1657.00 ± 331.47 2142.50 ± 587.61 Cmin Day 14 ng/ml 1678.50± 370.01 2287.50 ± 586.25 Cmin Day 15 ng/ml 1773.00 ± 424.13 2464.50 ±637.87 Mean Cmin ng/ml 1773.0000 ± 424.1288 2464.5000 ± 637.8704 Cavng/ml 1696.1655 ± 375.9869 2333.5010 ± 559.5159 Flux —  0.1025 ± 0.0737 0.1285 ± 0.2389 Swing —  0.1020 ± 0.0745  0.1395 ± 0.2843

Table 20 shows the geometric means and ratio of means and 90% confidenceintervals based on ANOVA of untransformed data of 2-hydroxyitraconazoleafter twice daily administration under fed conditions of 100 mg LOZANOCcapsule or 200 mg SPORANOX® (itraconazole).

TABLE 20 Geometric Means, ratio of means, and 90% CI of2-hydroxyitraconazole after twice-daily administration of itraconazoleAUC0-12 AUC0-24 AUC0-72 AUCinf Cmax (ng-hr/ml) (ng-hr/ml) (ng-hr/ml)(ng-hr/ml) (ng/ml) Geometric Means Based on ANOVA of Untransformed DataTest A 20472.40 40333.92 97855.05 194562.03 1936.16 Reference B 28102.5856463.79 150380.58 351817.47 2752.58 Ratio of Means, and 90% ConfidenceIntervals Based on ANOVA of Untransformed Data Ratio 0.7285 0.71430.6507 0.5530 0.7034 CI 0.6705-0.7864 0.6486-0.7800 0.5668-0.73460.2727-0.8333 0.6395-0.7673 p-value <0.0001 <0.0001 <0.0001 0.0136<0.0001

Table 21 shows the geometric means and ratio of means and 90% confidenceintervals based on ANOVA of ln-transformed data of 2-hydroxyitraconazoleafter twice daily administration under fed conditions of 100 mg LOZANOCcapsule or 200 mg SPORANOX® (itraconazole).

TABLE 21 Geometric Means, ratio of means, and 90% CI of2-hydroxyitraconazole after twice-daily administration of itraconazoleAUC0-12 AUC0-24 AUC0-72 AUCinf Cmax (ng-hr/ml) (ng-hr/ml) (ng-hr/ml)(ng-hr/ml) (ng/ml) Geometric Means Based on ANOVA of LN-Transformed DataTest A 20022.29 39429.62 94670.73 162427.06 1883.69 Reference B 27311.9754689.33 143845.88 306557.86 2666.26 Ratio of Means, and 90% ConfidenceIntervals Based on ANOVA of Ln-Transformed Data Ratio 0.7331 0.72100.6581 0.5298 0.7065 CI 0.6861-0.7833 0.6707-0.7750 0.5998-0.72220.4114-0.6824 0.6558-0.7611 p-value <0.0001 <0.0001 <0.0001 0.0005<0.0001

Example 8—Comparison of the Relative Bioavailability of LOZANOC 50 mgCapsules with SPORANOX® (Itraconazole) 100 mg Capsules Under FastingConditions

Study Rationale

This study compared the relative bioavailability of LOZANOC 50 mgcapsules with that of SPORANOX® (itraconazole) 100 mg capsules alreadyon the market in healthy volunteers. Subjects were given 50 mg or 100 mgdoses of LOZANOC, or 100 mg or 200 mg doses of SPORANOX® (itraconazole)under fasted conditions. The pharmacokinetics of both LOZANOC andSPORANOX® (itraconazole) were compared when each was given at twodifferent doses.

Twenty-four volunteers were enrolled in this randomized, multi-dose,four-treatment, four-way crossover study conducted to compare therelative bioavailability under fasting conditions of LOZANOC 50 mgcapsules when given as a single 50 mg dose and a single 100 mg dose(2×50 mg capsules) compared to SPORANOX® (itraconazole) 100 mg capsules,when given as a single 100 mg dose and a single 200 mg dose (2×100 mgcapsules). In each dosing period, either a single dose of 50 mg (1×50 mgcapsules) or 100 mg (2×50 mg capsules) LOZANOC or 100 mg (1×100 mgcapsule) or 200 mg (2×100 mg capsules) SPORANOX® (itraconazole) wasadministered to all subjects following an overnight fast of at least 10hours. The test formulation was LOZANOC 50 mg capsules and the referenceformulation was SPORANOX® (itraconazole) 100 mg capsules. The subjectsreceived each of the four treatments according to the four sequencedosing randomization schedule. There was a 7-day interval betweentreatments.

Blood samples were collected at 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0,6.0, 8.0, 10, 12, 24, 36, 48, and 72 hours after dosing. Pre-dosesamples were collected up to 60 minutes prior to dosing. The bloodsamples were centrifuged at approximately 2500 rpm for 15 minutes, andthe plasma collected for evaluation. Plasma samples were analyzed foritraconazole and 2-hydroxyitraconazole concentrations and agentpharmacokinetics.

The plasma concentration of itraconazole and 2-hydroxyitraconazole (ametabolite of itraconazole) were measured by fully validated analyticalprocedures. Statistical analysis was performed to evaluate the relativebioavailability for the two different doses of the Test product to thatof the two different doses of the Reference product under fastedconditions. The single-dose pharmacokinetics of the two different dosesof each product was analyzed to identify the dose rangingcharacteristics of each formulation.

LOZANOC (50 mg capsules) is a new formulation of oral itraconazolecapsules that, in pilot bioavailability studies in healthy normalvolunteers, has been shown to have comparable bioavailability toSPORANOX® (itraconazole) 100 mg capsules. (1,2). This study was designedbased on the known pharmacokinetics of both LOZANOC (previously known asSUBA-Itraconazole®) 50 mg capsules and SPORANOX® (itraconazole) 100 mgcapsules.

Study Design

In each period, subjects were given either:

Test A: A single dose of 50 mg (1×50 mg capsule) LOZANOC;

Test B: Two doses of 50 mg (2×50 mg capsule LOZANOC;

Reference C: One dose of 100 mg (1×100 mg capsule) SPORANOX®(itraconazole); or

Reference D: Two doses of 100 mg (2×100 mg capsule) SPORANOX®(itraconazole).

The drug was administered to all subjects following an overnight fast ofat least 10 hours. The subjects were randomized and received each of thefour treatments according to a four-sequence randomization schedule witha seven-day interval between each treatment.

Twenty-four (24) subjects were dosed (6 Test A, 6 Test B, 6 Reference C,6 Reference D) in Period I, 22 subjects were dosed (5 Test A, 6 Test B,6 Reference C, 5 Reference D) in Period II, 23 subjects were dosed (5Test A, 6 Test B, 6 Reference C, 6 Reference D) in Period III on, and 23subjects were dosed (6 Test A, 5 Test B, 6 Reference C, 6 Reference D)in Period IV. Data from subjects who completed at least two periods ofthe study were included in the statistical analysis.

The subjects were monitored throughout the study for any adverse events.No serious adverse events were reported.

Pharmacokinetic Analysis

Concentrations of itraconazole and hydroxyitraconazole in plasma weredetermined at using fully validated analytical methods as described inExample 6.

The following comparisons were computed.

-   -   Test A v Reference C (N=22)−comparison of a single 50 mg dose of        LOZANOC capsule with a single 100 mg dose of SPORANOX®        (itraconazole) capsule in the fasted state.    -   Test B v Reference D (N=22)−comparison of a single 100 mg dose        of LOZANOC (2×50 mg capsules) with a single 200 mg dose of        SPORANOX® (itraconazole) (2×100 mg capsules) in the fasted        state.    -   Test A v Test B (N=22)−comparison of a single 50 mg dose of        LOZANOC capsule with a single 100 mg dose of LOZANOC (2×50 mg        capsules) in the fasted state.    -   Reference C v Reference D (N=22)−comparison of a single 100 mg        dose of SPORANOX® (itraconazole) capsule with a single 200 mg        dose of SPORANOX® (itraconazole) (2×100 mg capsules) in the        fasted state

The first two sets of analysis primary determination of pharmacokineticequivalence of LOZANOC compared with twice the dose of SPORANOX®(itraconazole) in the fasted state was based on the log-transformed datafor itraconazole. If the 90% confidence interval for the test/referenceratio for AUCt, AUCinf, and Cmax for itraconazole fall within the range80.00-125.00%, then equivalence has been demonstrated.

The relative bioavailability of a single 50 mg dose of the test productcompared to a single 100 mg dose of the test product (A v B), and therelative bioavailability of a single 100 mg dose of the referenceproduct compared to a single 200 mg dose of the reference product (C vD) are presented for informational purposes. If the ratio of mean Cmaxand mean AUC for A/B or C/D are approximately 0.5 then it may beconsidered that the single dose pharmacokinetics of itraconazole areapproximately linear in the dose range tested for that specificformulation.

The same analysis was performed on the hydroxyitraconazole data forinformational purposes.

For each serum sample, the mean concentration of itraconazole in theserum for each agent and dose over time was determined. Thepharmacokinetic parameters were also determined for each agent and dose.

FIGS. 25 (linear plot) and 26 (ln-linear plot) show the meanconcentration of itraconazole in the blood serum over time.

FIGS. 27 (linear plot) and 28 (ln-linear plot) show the meanconcentration of 2-hydroxyitraconazole in the blood serum over time foreach itraconazole agent and dose.

Table 22 summarizes the pharmacokinetic parameters (untransformed) ofitraconazole for the various agents and doses described above.

TABLE 22 Pharmacokinetic Parameters of Itraconazole Agents Summary ofPharmacokinetic Parameters Pharmacokinetic Arithmetic mean ± SD (% CV)Parameter Test A Test B Reference C Reference D AUCt 714.9464 ± 293.21841876.8254 ± 733.005  789.3709 ± 318.1479 2015.6652 ± 1332.6396 (ng ·hr/ml) (41.0126) (39.0556) (40.3040) (66.1141) AUCinf 773.1397 ±335.4541 2041.3007 ± 798.8421 853.0783 ± 347.3570 2222.5795 ± 1488.8634(ng · hr/ml) (43.3885) (39.1340) (40.7181) (66.9881) Cmax 79.5500 ±29.8543 178.0000 ± 71.4344 64.6348 ± 28.0251 164.6043 ± 111.6715 (ng/ml)(37.5289) (40.1317) (43.3592) (67.8423) Tmax 2.8432 ± 0.9565  3.4783 ±0.9229 3.2181 ± 0.8218 3.3275 ± 0.8752 (hr) (33.6408) (26.5339)(25.5352) (26.3009) Median Tmax  2.7500  3.0000  3.0000  3.0000 (hr) Ke0.0372 ± 0.0085  0.0362 ± 0.0093 0.0381 ± 0.0127 0.0337 ± 0.0082 (1/hr)(22.8796) (25.7917) (33.2712) (24.3801) Elimhalf 19.5320 ± 4.2499 20.3115 ± 4.9224 19.6020 ± 4.8500  21.6492 ± 4.7155  (hr) (21.7589)(24.2344) (24.7426) (21.7812)

Table 23 shows the geometric means based on ANOVA of untransformed andLn-transformed data for the various comparisons of itraconazole agentsand doses.

TABLE 23 Geometric Means of Itraconazole Agents Geometric Means Based onANOVA of Untransformed and Ln-Transformed Data Untransformed DataLn-Transformed Data AUCt AUCinf Cmax AUCt AUCinf Cmax (ng · hr/ml) (ng ·hr/ml) (ng/ml) (ng · hr/ml) (ng · hr/ml) (ng/ml) Test A 670.27 725.0374.96 635.81 683.56 70.72 Test B 1836.35 1995.40 175.00 1674.84 1814.68156.50 Reference C 823.62 892.81 66.87 744.98 805.34 59.45 Reference D2029.15 2236.33 164.90 1570.63 1722.77 122.01

Table 24 shows the ratio of means and 90% confidence intervals based onANOVA of untransformed and Ln-transformed data for Test A (1×50 mgLOZANOC) v Reference C (1×100 mg SPORANOX® (itraconazole)).

TABLE 24 Ratio of Means and Confidence Intervals for Test A v. ReferenceC Ratio of Means, and 90% Confidence Intervals Based on ANOVA ofUntransformed and Ln-Transformed Data Test A (1 × 50 mg) v Reference C(1 × 100 mg) Untransformed Data Ln-Transformed Data AUCt AUCinf CmaxAUCt AUCinf Cmax (ng · hr/ml) (ng · hr/ml) (ng/ml) (ng · hr/ml) (ng ·hr/ml) (ng/ml) Ratio 0.8138 0.8121 1.1211 0.8535 0.8488 1.1894 CI0.4279-1.1997 0.4221-1.2020 0.6983-1.5439 0.7035-1.0354 0.7007-1.02820.9517-1.4865 p-value 0.4234 0.4240 0.6341 0.1758 0.1584 0.1987

When a single-dose of 50 mg LOZANOC is given in the fasted state, thepeak and overall bioavailability as measured by Cmax and AUC isapproximately 120% and 85% respectively, of that seen following a single100 mg dose of SPORANOX® (itraconazole) capsules under fastingconditions. Based on the statistical analysis of itraconazole, thecomparison of a single 50 mg dose of capsule LOZANOC with a single 100mg dose of SPORANOX® (itraconazole) capsule in the fasted state does notmeet the 90% confidence interval (CI) for log-transformed AUCt, AUCinf,and Cmax.

Table 25 shows the ratio of means and 90% Confidence Interval based onANOVA of untransformed and ln-transformed data of Test B (2×50 mgLOZANOC) and Reference D (2×100 mg SPORANOX® (itraconazole)).

TABLE 25 Ratio of Means and Confidence Intervals for Test B v. ReferenceD Ratio of Means, and 90% Confidence Intervals Based on ANOVA ofUntransformed and Ln-Transformed Data (Test B 2 × 50 mg) v Reference D(2 × 100 mg) Untransformed Data Ln-Transformed Data AUCt AUCinf CmaxAUCt AUCinf Cmax (ng · hr/ml) (ng · hr/ml) (ng/ml) (ng · hr/ml) (ng ·hr/ml) (ng/ml) Ratio 0.9050 0.8923 1.0612 1.0664 1.0534 1.2827 CI0.7505-1.0595 0.7387-1.0458 0.8921-1.2304 0.8813-1.2903 0.8718-1.27271.0295-1.5982 p-value 0.3084 0.2458 0.5475 0.5756 0.6479 0.0634

When a single dose of 100 mg of LOZANOC (2×50 mg capsules) is given inthe fasted state the peak and overall bioavailability as measured byCmax and AUC is approximately 130% and 106% respectively, of that seenfollowing a single 200 mg dose of SPORANOX® (itraconazole) (2×100 mgcapsules) under fasting conditions. Based on the statistical analysis ofitraconazole, the comparison of a single 100 mg dose of capsule LOZANOCwith a single 200 mg dose of SPORANOX® (itraconazole) capsule in thefasted state does not meet the 90% Confidence Interval forlog-transformed AUCt, AUCinf, and Cmax.

Table 26 shows the ratio of means and 90% Confidence Interval based onANOVA of untransformed and Ln-transformed data of Test A (1×50 mgLOZANOC) and Test B (2×50 mg LOZANOC).

TABLE 26 Ratio of Means and Confidence Intervals for Test A v. Test BRatio of Means, and 90% Confidence Intervals Based on ANOVA ofUntransformed and Ln-Transformed Data Test A (1 × 50 mg) v Test B (2 ×50 mg) Untransformed Data Ln-Transformed Data AUCt AUCinf Cmax AUCtAUCinf Cmax (ng · hr/ml) (ng · hr/ml) (ng/ml) (ng · hr/ml) (ng · hr/ml)(ng/ml) Ratio 0.3650 0.3634 0.4284 0.3796 0.3767 0.4519 CI 0.1934-0.53660.1904-0.5363 0.2682-0.5886 0.3134-0.4598 0.3115-0.4556 0.3623-0.5637p-value <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001

When a single 50 mg dose of LOZANOC capsules is given in the fastedstate, the ratio of mean, Cmax is approximately 45% of that seenfollowing a single 100 mg dose of LOZANOC (2×50 mg capsules) in thefasted state.

Table 27 shows the ratio of means and 90% Confidence Interval based onANOVA of untransformed and ln-transformed data of Reference C (1×100 mgSPORANOX® (itraconazole)) and Reference D (2×100 mg SPORANOX®(itraconazole)).

TABLE 27 Ratio of Means and Confidence Intervals for Reference C v.Reference D Ratio of Means, and 90% Confidence Intervals Based on ANOVAof Untransformed and Ln-Transformed Data Reference C (1 × 100 mg) vReference D (2 × 100 mg) Untransformed Data Ln-Transformed Data AUCtAUCinf Cmax AUCt AUCinf Cmax (ng · hr/ml) (ng · hr/ml) (ng/ml) (ng ·hr/ml) (ng · hr/ml) (ng/ml) Ratio 0.4059 0.3992 0.4055 0.4743 0.46750.4873 CI 0.2520-0.5598 0.2463-0.5522 0.2371-0.5739 0.3923-0.57350.3872-0.5644 0.3915-0.6066 p-value <0.0001 <0.0001 <0.0001 <0.0001<0.0001 <0.0001

When a single 100 mg dose of SPORANOX® (itraconazole) capsules is givenin the fasted state, the ratio of mean Cmax and mean AUC areapproximately 50% of that seen following a single 200 mg dose ofSPORANOX® (itraconazole) (2×100 mg capsules) in the fasted state.

Table 28 summarizes the pharmacokinetic parameters (untransformed) of2-hydroxyitraconazole after administration of the various itraconazoleagents and doses described above.

Table 29 shows the ratio of means and 90% Confidence Interval based onANOVA of untransformed and ln-transformed data for the comparisonsperformed in this study. As would be anticipated, the comparativeresults of the metabolite data (2-hydroxyitraconazole) are consistent tothat observed with the parental product (itraconazole).

TABLE 28 Summary of Pharmacokinetic Parameters for 2-hydroxyitraconazoleSummary of Pharmacokinetic Parameters Pharmacokinetic Arithmetic mean ±SD (% CV) Parameter Test A Test B Reference C Reference D AUCt 1514.7223± 630.4316 4162.1861 ± 1862.0149 1765.8720 ± 694.9582 4455.4271 ±2891.5105 (ng · hr/ml) (41.6203) (44.7365) (39.3550) (64.8986) AUCinf1529.9022 ± 637.1077 4215.9561 ± 1883.7742 1792.6811 ± 704.05044546.9988 ± 2972.9973 (ng · hr/ml) (41.6437) (44.6820) (39.2736)(65.3837) Cmax 136.6273 ± 39.1386 246.4565 ± 73.8615  123.4500 ± 36.6698234.9087 ± 117.1553 (ng/ml) (28.6463) (29.9694) (29.7042) (49.8727) Tmax 3.1394 ± 0.8621 3.8913 ± 0.8251  3.6250 ± 0.7974 3.8493 ± 0.8320 (hr)(27.4617) (21.2043) (21.9976) (21.6142) Median Tmax  3.0000  4.0000 4.0000  4.0000 (hr) Ke  0.0992 ± 0.0252 0.0783 ± 0.0263  0.0762 ±0.0253 0.0681 ± 0.0230 (1/hr) (25.3748) (33.5392) (33.2301) (33.7645)Elimhalf  7.4683 ± 2.0431 9.7261 ± 2.9654 10.5333 ± 5.4746 11.2233 ±3.5688  (hr) (27.3569) (30.4886) (51.9749) (31.7976)

Based on the statistical analysis of itraconazole under fastedconditions, using the comparisons of Test A (1×50 mg LOZANOC capsules) vReference C (1×100 mg SPORANOX® (itraconazole) capsules) and Test B(2×50 mg LOZANOC capsules) v Reference D (2×100 mg SPORANOX®(itraconazole) capsules), LOZANOC capsules does not meet the 90%Confidence Interval for log transformed AUCt, AUCinf, and Cmax.

For both the test and reference formulations, doubling the dose resultedin approximately a two-fold increase in bioavailability as measured byCmax. This would suggest that itraconazole follows non-linearpharmacokinetics.

TABLE 29 Ratio of Means and Confidence Intervals for2-hydroxyitraconazole Geometric Means, Ratio of Means, and 90%Confidence Intervals Based on ANOVA of Untransformed and Ln-TransformedData Untransformed Data Ln-Transformed Data AUCt AUCinf Cmax AUCt AUCinfCmax (ng · hr/ml) (ng · hr/ml) (ng/ml) (ng · hr/ml) (ng · hr/ml) (ng/ml)Test A 1429.73 1443.12 132.77 1353.80 1367.47 128.50 Test B 4079.744131.68 244.61 3657.49 3703.58 232.95 Reference C 1765.87 1792.68 123.451634.24 1660.54 118.12 Reference D 4486.28 4577.18 235.76 3499.973564.93 203.72 Test A (1 × 50 mg) v Reference C (1 × 100 mg) Ratio0.8096 0.8050 1.0755 0.8284 0.8235 1.0879 CI 0.4164-1.2029 0.4089-1.20110.8248-1.3263 0.6780-1.0122 0.6746-1.0054 0.9189-1.2880 p-value 0.42200.4142 0.6168 0.1217 0.1092 0.4081 Test B (2 × 50 mg) v Reference D (2 ×100 mg) Ratio 0.9094 0.9027 1.0375 1.0450 1.0389 1.1435 CI 0.7545-1.06430.7474-1.0579 0.9061-1.1689 0.8551-1.2770 0.8509-1.2685 0.9657-1.3540p-value 0.3324 0.2992 0.6351 0.7152 0.7507 0.1901 Test A (1 × 50 mg) vTest B (2 × 50 mg) Ratio 0.3504 0.3493 0.5428 0.3701 0.3692 0.5516 CI0.1792-0.5217 0.1764-0.5222 0.4155-0.6701 0.3026-0.4528 0.3021-0.45130.4654-0.6537 p-value <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001Reference C (1 × 100 mg) v Reference D (2 × 100 mg) Ratio 0.3936 0.39170.5236 0.4669 0.4658 0.5798 CI 0.2414-0.5458 0.2391-0.5442 0.3945-0.65270.3834-0.5686 0.3828-0.5668 0.4911-0.6845 p-value <0.0001 <0.0001<0.0001 <0.0001 <0.0001 <0.0001

Example 9—Comparison of the Relative Bioavailability of LOZANOC 50 mgCapsules with SPORANOX® (Itraconazole) 100 mg Capsules Under Fasting andFed Conditions

Study Rationale

This study evaluated the relative bioavailability of LOZANOC 50 mgcapsules with that of SPORANOX® (itraconazole) 100 mg capsules. Thepharmacokinetics of both LOZANOC and SPORANOX® (itraconazole) werecompared when administered to subjects under fasted and fed conditions.

This randomized, single-dose, four-treatment, four-period, crossoverstudy was conducted to compare single doses of LOZANOC 50 mg capsules toSPORANOX® (itraconazole) 100 mg capsules under fasted and fedconditions. The study was conducted with 36 (35 completing at least twoperiods of the study) healthy, nontobacco using, adults. In each studyperiod, a single dose (1×50 mg LOZANOC capsule or 1×100 mg SPORANOX®(itraconazole) capsule) was administered to all subjects. In two of thestudy periods subjects were dosed (with either a test or referenceproduct) following an overnight fast of at least 10 hours. In the othertwo periods, subjects were dosed (with either a test or referenceproduct) following a standardized high fat, high calorie breakfastpreceded by an overnight fast of at least 10 hours. The test formulationwas LOZANOC 50 mg capsules and the reference formulation was SPORANOX®(itraconazole) 100 mg capsules. The subjects received the test productin two of the study periods and the reference product in the other twostudy periods; the order of administration was according to the foursequence dosing randomization schedule. There was a 7-day intervalbetween treatments.

Blood samples were collected at 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0,6.0, 8.0, 10, 12, 24, 36, 48, and 72 hours after dosing. Pre-dosesamples were collected up to 60 minutes prior to dosing. The bloodsamples were centrifuged at approximately 2500 rpm for 15 minutes, andthe plasma collected. The plasma concentration of itraconazole and2-hydroxyitraconazole (a metabolite of itraconazole) were measured byfully validated analytical procedures. Statistical analysis wasperformed to evaluate the relative bioavailability for the test andreference agents under fasting or fed conditions. Plasma samples wereanalyzed for itraconazole and 2-hydroxyitraconazole concentrations.

Study Design

In each period, subjects were given either:

-   -   Test A: A single dose of 50 mg (1×50 mg capsule) LOZANOC;        fasting conditions;    -   Test B: A single dose of 50 mg (1×50 mg capsule) LOZANOC; fed        conditions; Reference C: One dose of 100 mg (1×100 mg capsule)        SPORANOX® (itraconazole); fasting conditions; or    -   Reference D: Two doses of 100 mg (2×100 mg capsule) SPORANOX®        (itraconazole); fed conditions.

Thirty-six (36) subjects were dosed (9 Test A, 9 Test B, 9 Reference C,9 Reference D) in Period I, 35 subjects were dosed (9 Test A, 9 Test B,9 Reference C, 8 Reference D) in Period II, 35 subjects were dosed (9Test A, 8 Test B, 9 Reference C, 9 Reference D) in Period III, and 34subjects were dosed (9 Test A, 9 Test B, 7 Reference C, 9 Reference D)in Period IV.

The subjects were monitored throughout the study for any adverse events.No serious adverse events were reported.

Pharmacokinetic Analysis

Concentrations of itraconazole and hydroxyitraconazole in plasma weredetermined at using fully validated analytical methods as described inExample 6. Subjects who completed at least 2 periods of the study wereincluded in the final data set.

The following comparisons were computed.

-   -   Test A v Reference C—comparison of a single 50 mg dose of        LOZANOC capsule with a single 100 mg dose of SPORANOX®        (itraconazole) capsule in the fasting state.    -   Test B v Reference D—comparison of a single 50 mg dose of        LOZANOC (1×50 mg capsules) with a single 100 mg dose of        SPORANOX® (itraconazole) (1×100 mg capsules) in the fed state.    -   Test A v Test B—comparison of a single 50 mg dose of LOZANOC        capsule in the fasting state with a single 50 mg dose of LOZANOC        (1×50 mg capsule) in the fed state.    -   Reference C v Reference D—comparison of a single 100 mg dose of        SPORANOX® (itraconazole) capsule in the fasting state with a        single 100 mg dose of SPORANOX® (itraconazole) (1×100 mg        capsules) in the fed state    -   Test A v Reference D—comparison of a single 50 mg dose of        LOZANOC capsule in the fasting state compared with 100 mg dose        of SPORANOX® (itraconazole) (1×100 mg capsules) in the fed        state.

Primary determination of pharmacokinetic equivalence was based on thelog-transformed data for itraconazole. If the 90% confidence intervalfor the test/reference ratio for AUCt, AUCinf, and Cmax for itraconazolefalls within the range 80.00-125.00%, then equivalence has beendemonstrated. Equivalence was tested under fasting conditions.

The effect of food on each formulation was based on the log-transformeddata for itraconazole by comparing Test A v Test B and Reference C vReference D. If the 90% confidence interval for the test/reference ratiofor AUCt, AUCinf, and Cmax for itraconazole falls within the range80.00-125.00%, in the fed state compared to the fasted state then foodwas considered not to have any effect on the bioavailability of thatformulation.

The relative bioavailability of a single 50 mg capsule dose of the testproduct under fasted conditions compared to a single 100 mg capsule doseof the reference product under fed conditions (Test A v Reference D) waspresented for information purposes.

The same analysis was performed on the hydroxyitraconazole data forinformational purposes.

For each serum sample, the mean concentration of itraconazole over timeand the pharmacokinetic parameters were determined after administrationof the agents under fasted or fed conditions.

FIGS. 29 (linear plot) and 30 (ln-linear plot) show the meanconcentration of itraconazole in fasted and fed subjects in the bloodserum over time.

FIGS. 31 (linear plot) and 32 (ln-linear plot) show the meanconcentration of 2-hydroxyitraconazole in fasted and fed subjects in theblood serum over time.

Table 30 summarizes the pharmacokinetic parameters (untransformed) ofitraconazole for the agents administered under fasted and fed conditionsdescribed above.

TABLE 30 Summary of Pharmacokinetic Parameters of Itraconazole in Fastedand Fed Conditions Summary of Pharmacokinetic Parameters PharmacokineticArithmetic mean ± SD (% CV) Parameter Test A Test B Reference CReference D AUCt 804.51 ± 483.41 604.14 ± 417.14 1147.09 ± 719.49 855.51± 581.34 (ng · hr/ml) (60.09) (69.05) (62.72) (67.95) AUCinf 898.33 ±607.78 684.05 ± 541.50 1208.35 ± 843.46 959.01 ± 686.94 (ng · hr/ml)(67.66) (79.16) (69.80) (71.63) Cmax 80.17 ± 38.71 39.04 ± 25.79  87.62± 54.98 63.17 ± 41.89 (ng/ml) (48.29) (66.05) (62.76) (66.32) Tmax 3.03± 1.16 7.64 ± 3.81  3.16 ± 0.94 5.71 ± 1.80 (hr) (38.35) (49.85) (29.58)(31.57) Median Tmax  2.50  6.00  3.00  5.00 (hr) Ke 0.04 ± 0.01 0.04 ±0.01  0.03 ± 0.01 0.04 ± 0.01 (1/hr) (31.85) (33.67) (28.25) (31.94)Elimhalf 20.74 ± 6.65  19.14 ± 5.83  21.52 ± 5.66 19.86 ± 5.87  (hr)(32.07) (30.47) (26.32) (29.58)

Table 31 shows the geometric means based on ANOVA of untransformed andln-transformed data for the itraconazole agents tested in this studyunder fasting and fed conditions.

TABLE 31 Geometric Means of Itraconazole Agents in Fasted and FedConditions c Geometric Means Based on ANOVA of Untransformed andLn-Transformed Data Untransformed Data Ln-Transformed Data AUCt AUCinfCmax AUCt AUCinf Cmax (ng · hr/ml) (ng · hr/ml) (ng/ml) (ng · hr/ml) (ng· hr/ml) (ng/ml) Test A 804.08 897.51 80.12 676.00 735.77 69.92 Test B644.86 738.20 40.40 533.30 588.76 32.76 Reference C 1137.56 1238.7887.19 927.60 1011.63 71.26 Reference D 879.58 987.71 64.38 692.62 762.6450.11

Table 32 shows the ratio of means and 90% Confidence Interval based onANOVA of untransformed and ln-transformed data for Test A (50 mg dose ofLOZANOC capsule) with Reference C (100 mg dose of SPORANOX®(itraconazole) capsule) in the fasting state.

TABLE 32 Ratio of Means and Confidence Intervals for Test A v ReferenceC Ratio of Means, and 90% Confidence Intervals Based on ANOVA ofUntransformed and Ln-Transformed Data Test A (fasted) v Reference C(fasted) Untransformed Data Ln-Transformed Data AUCt AUCinf Cmax AUCtAUCinf Cmax (ng · hr/ml) (ng · hr/ml) (ng/ml) (ng · hr/ml) (ng · hr/ml)(ng/ml) Ratio 0.7068 0.7245 0.9189 0.7288 0.7273 0.9813 CI 0.6069-0.80680.6188-0.8303 0.7892-1.0485 0.6299-0.8432 0.6268-08440 0.8113-1.1870p-value <0.0001 <0.0001 0.3013 0.0005 0.0006 0.8694

This comparison showed that the mean peak plasma concentration (Cmax) ofa single dose of the Test product LOZANOC 50 mg capsules under fastedconditions are equivalent to that of the Reference product SPORANOX®(itraconazole) 100 mg capsules under fasted conditions.

Table 33 shows the ratio of means and 90% Confidence Interval based onANOVA of untransformed and ln-transformed data for Test B (50 mg dose ofLOZANOC capsule) with Reference D (100 mg dose of SPORANOX®(itraconazole) capsule) in the fed state.

TABLE 33 Ratio of Means and Confidence Intervals for Test B v ReferenceD Ratio of Means, and 90% Confidence Intervals Based on ANOVA ofUntransformed and Ln-Transformed Data Test B (fed) v Reference D (fed)Untransformed Data Ln-Transformed Data AUCt AUCinf Cmax AUCt AUCinf Cmax(ng · hr/ml) (ng · hr/ml) (ng/ml) (ng · hr/ml) (ng · hr/ml) (ng/ml)Ratio 0.7331 0.7474 0.6274 0.7700 0.7720 0.6538 CI 0.6017-0.86460.6152-0.8796 0.4489-0.8060 0.6639-0.8930 0.6656-0.8954 0.5388-0.7934p-value 0.0011 0.0020 0.0008 0.0043 0.0047 0.0004

When a single 50 mg dose of the LOZANOC 50 mg capsules is givenfollowing a high fat meal, the peak and overall bioavailability asmeasured by Cmax and AUC is approximately 70% of that seen following asingle 100 mg capsule dose of the Reference product (100 mg dose ofSPORANOX® (itraconazole) under fed conditions.

Table 34 shows the ratio of means and 90% Confidence Interval based onANOVA of untransformed and ln-transformed data for Test A (50 mg dose ofLOZANOC capsule under the fasted state) with Test B (50 mg dose ofLOZANOC capsule under the fed state).

TABLE 34 Ratio of Means and Confidence Intervals for Test B v ReferenceD Ratio of Means, and 90% Confidence Intervals Based on ANOVA ofUntransformed and Ln-Transformed Data Test A (fasted) v Test B (fed)Untransformed Data Ln-Transformed Data AUCt AUCinf Cmax AUCt AUCinf Cmax(ng · hr/ml) (ng · hr/ml) (ng/ml) (ng · hr/ml) (ng · hr/ml) (ng/ml)Ratio 1.2469 1.2158 1.9833 1.2676 1.2497 2.1342 CI 1.0683-1.42551.0396-1.3920 1.6998-2.2668 1.0935-1.4693 1.0781-1.4487 1.7600-2.5880p-value 0.0239 0.0447 <0.0001 0.0090 0.0139 <0.0001

When given in the fasted state, the single dose Cmax of the Test product(50 mg dose of LOZANOC capsule) is approximately twice that of the samedose of LOZANOC capsule given following a high fat meal. Overallbioavailability as measured by AUC is approximately 25% higher in thefasted state compared to the fed state. Time to peak concentration(Tmax) increases from around 2.5 hours to 6 hours when LOZANOC 50 mgcapsules are given with a high fat meal.

Table 35 shows the ratio of means and 90% Confidence Interval based onANOVA of untransformed and ln-transformed data for Reference C (100 mgdose of SPORANOX® (itraconazole) under the fasted state) with ReferenceD (100 mg dose of SPORANOX® (itraconazole) under the fed state).

TABLE 35 Ratio of Means and Confidence Intervals for Reference C vReference D Ratio of Means, and 90% Confidence Intervals Based on ANOVAof Untransformed and Ln-Transformed Data Reference C (fasted) vReference D (fed) Untransformed Data Ln-Transformed Data AUCt AUCinfCmax AUCt AUCinf Cmax (ng · hr/ml) (ng · hr/ml) (ng/ml) (ng · hr/ml) (ng· hr/ml) (ng/ml) Ratio 1.2933 1.2542 1.3542 1.3393 1.3265 1.4220 CI1.1624-1.4242 1.1199-1.3884 1.1765-1.5320 1.1555-1.5523 1.1410-1.54211.1728-1.7240 p-value 0.0003 0.0022 0.0013 0.0014 0.0024 0.0031

When given in the fasted state, the single dose Cmax for SPORANOX®(itraconazole) 100 mg capsules is approximately 40% higher and the AUCis approximately 30% higher than that of the same dose of SPORANOX®(itraconazole) 100 mg capsules given following a high fat meal. Time topeak concentration (Tmax) increases from around 3 hours to 5 hours whenSPORANOX® (itraconazole) 100 mg capsules are given following a high fatmeal.

Table 36 shows the ratio of means and 90% Confidence Interval based onANOVA of untransformed and ln-transformed data for Test A (50 mg dose ofLOZANOC capsule under the fasted state) with Reference D (100 mg dose ofSPORANOX® (itraconazole) under the fed state).

TABLE 36 Ratio of Means and Confidence Intervals for Test A v ReferenceD Ratio of Means, and 90% Confidence Intervals Based on ANOVA ofUntransformed and Ln-Transformed Data Test A (fasted) v Reference D(fed) Untransformed Data Ln-Transformed Data AUCt AUCinf Cmax AUCtAUCinf Cmax (ng · hr/ml) (ng · hr/ml) (ng/ml) (ng · hr/ml) (ng · hr/ml)(ng/ml) Ratio 0.9142 0.9087 1.2444 0.9760 0.9648 1.3954 CI 0.7847-1.04360.7785-1.0388 1.0686-1.4202 0.8434-1.1294 0.8337-1.1164 1.1533-1.6882p-value 0.2734 0.2467 0.0231 0.7829 0.6841 0.0046

The overall bioavailability (AUC) of a single dose of LOZANOC 50 mgcapsules under fasted conditions are equivalent to that of the Referenceproduct SPORANOX® (itraconazole) 100 mg capsules when given under fedconditions, although the Cmax is approximately 30% higher.

Table 37 summarizes the pharmacokinetic parameters (untransformed) of2-hydroxyitraconazole metabolized from the Test and Reference productsadministered under fasting and fed conditions.

TABLE 37 Summary of Pharmacokinetic Parameters for 2-hydroxyitraconazoleunder fasted and fed conditions Summary of Pharmacokinetic ParametersPharmacokinetic Arithmetic mean ± SD (% CV) Parameter Test A Test BReference C Reference D AUCt 1611.12 ± 851.06 1224.98 ± 800.59  2262.65± 1307.43 1760.13 ± 1233.23 (ng · hr/ml) (52.82) (65.36) (57.78) (70.06)AUCinf 1646.61 ± 907.11 1263.28 ± 874.05  2329.99 ± 1404.64 1814.12 ±1304.81 (ng · hr/ml) (55.09) (69.19) (60.29) (71.92) Cmax 121.09 ± 34.7763.30 ± 27.76 135.48 ± 49.82  94.13 ± 48.79 (ng/ml) (28.71) (43.86)(36.78) (51.83) Tmax  3.46 ± 1.34 9.54 ± 5.81 3.59 ± 0.87 7.11 ± 3.59(hr) (38.77) (60.86) (24.13) (50.42) Median Tmax  3.00  6.00  4.00  6.00(hr) Ke  0.09 ± 0.03 0.09 ± 0.03 0.07 ± 0.02 0.09 ± 0.03 (1/hr) (34.24)(32.59) (29.09) (33.97) Elimhalf  8.75 ± 3.38 8.44 ± 3.57 10.71 ± 3.50 8.98 ± 3.77 (hr) (38.67) (42.34) (32.63) (41.97)

Table 38 shows the ratio of means and 90% Confidence Interval based onANOVA of untransformed and ln-transformed data for the comparisonsperformed in this study. As would be anticipated, the comparativeresults of the metabolite data (2-hydroxyitraconazole) are consistent tothat observed with the parental product (itraconazole).

TABLE 38 Ratio of Means and Confidence Intervals for2-hydroxyitraconazole Geometric Means, Ratio of Means, and 90%Confidence Intervals Based on ANOVA of Untransformed and Ln-TransformedData Untransformed Data Ln-Transformed Data AUCt AUCinf Cmax AUCt AUCinfCmax (ng · hr/ml) (ng · hr/ml) (ng/ml) (ng · hr/ml) (ng · hr/ml) (ng/ml)Test A 1614.60 1650.23 121.27 1393.44 1415.14 115.92 Test B 1228.801267.09 63.42 1027.06 1047.24 57.84 Reference C 2247.52 2313.99 135.431864.27 1906.30 123.78 Reference D 1764.19 1818.55 94.28 1356.53 1384.9782.20 Test A (fasted) v Reference C (fasted) Ratio 0.7184 0.7132 0.89550.7474 0.7424 0.9365 CI 0.6181-0.8187 0.6137-0.8127 0.8034-0.98760.6429-0.8690 0.6394-0.8619 0.8065-10875 p-value <0.0001 <0.0001 0.06250.0018 0.0013 0.4678 Test B (fed) v Reference D (fed) Ratio 0.69650.6968 0.6727 0.7571 0.7562 0.7037 CI 0.5701-0.8229 0.5715-0.82200.5418-0.8036 0.6522-0.8789 0.6523-0.8765 0.6070-0.8159 p-value 0.00010.0001 <0.0001 0.0025 0.0022 0.0002 Test A (fasted) v Test B (fed) Ratio1.3140 1.3024 1.9121 1.3567 1.3513 2.0039 CI 1.1325-1.4954 1.1226-1.48221.7175-2.1068 1.1688-1.5749 1.1658-1.5664 1.7284-2.3234 p-value 0.00500.0063 <0.0001 0.0010 0.0010 <0.0001 Reference v Reference D (fed) C(fasted) Ratio 1.2740 1.2724 1.4364 1.3743 1.3764 1.5059 CI1.1462-1.4017 1.1458-1.3990 1.3040-1.5687 1.1820-1.5979 1.1856-1.59801.2968-1.7487 p-value 0.006 0.0005 <0.0001 0.0007 0.0006 <0.0001 Test A(fasted) v Reference D (fed) Ratio 0.9152 0.9074 1.2862 1.0272 1.02181.4102 CI 0.7888-1.0416 0.7822-1.0327 1.1553-1.4172 0.8849-1.19240.8815-1.1844 1.2163-1.6350 p-value 0.2680 0.2228 0.0005 0.7656 0.80910.0002

Example 10—Bioavailability Study Comparing 50 mg LOZANOC Itraconazole toSPORANOX® (Itraconazole) Under Fed and Fasted Conditions

Study Rationale

This study was performed to determine the relative bioavailability of anew formulation of itraconazole capsules (SUBA®-itraconazole), 50 mgunder fed and fasted conditions compared to currently marketeditraconazole capsules (SPORANOX® purchased from a European state), 100mg under fed and fasted conditions when administered to healthy male andfemale subjects as a single oral dose. SPORANOX® capsules demonstratehigh between-patient variability in the absorption of itraconazole,where occasionally very high or sub-therapeutic plasma levels areexperienced. Due to higher bioavailability, a 50 mg dose of LOZANOC isexpected to result in similar exposure to itraconazole as seen followinga 100 mg dose of SPORANOX®. A fed/fasted comparison was included in thestudy to investigate the effect of food on the new LOZANOC capsules dueto the significant impact that food is known to have on thebioavailability of the current marketed SPORANOX® capsules.

Study Design

This was a randomized, single dose, open-label, 4-way crossover,relative bioavailability study in healthy male and female subjects. Atotal of 36 subjects participated in the study. Thirty-five subjectscompleted the study. Screening was performed in the 28-day period priorto the first dose. Each subject participated in 4 treatment periods,residing at the CRU from Day −1 (the day before dosing) to Day 3 (48hours post dose). Dosing occurred on Day 1 for each subject. Subjectsthen returned for an outpatient visit on Day 4 (72 hours post dose).There was a minimum of 7 days between each dose administration.

Study Treatments

Test Formulation: capsules containing 50 mg itraconazole (LOZANOC).

Reference Formulation: 100 mg capsules SPORANOX® (itraconazole)

Treatment A: LOZANOC capsules, 50 mg administered following at least a10-hour overnight fast.

Treatment B: LOZANOC capsules, 50 mg administered following a high-fat,high-calorie breakfast after at least a 10-hour fast.

Treatment C: SPORANOX® (itraconazole) capsules, 100 mg administeredfollowing at least a 10-hour overnight fast.

Treatment D: SPORANOX® (itraconazole) capsules, 100 mg administeredfollowing a high-fat, high-calorie breakfast after at least a 10-hourfast.

Each subject received a total of 4 doses of itraconazole during thestudy (2 doses of LOZANOC capsules and 2 doses of SPORANOX®).

Blood samples were collected pre-dose and at the following times afteradministration of each dose: 0.5 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10,12, 16, 24, 36, 48 and 72 hours. Following collection, plasma wasseparated from blood cells by centrifugation. All plasma samples werestored frozen at −20.0 (±5° C.) until analysis.

Sample Analysis

The analysis of itraconazole and hydroxyitraconazole in plasma sampleswas performed by the Department of Bioanalytical Services at CovanceLaboratories Europe (CLE), Harrogate, UK using a validated analyticalmethod. The plasma samples were prepared by solid phase extraction. Thecentrifuged eluates were quantified by liquid chromatography with tandemmass spectrometric detection (LC-MS/MS).

Pharmacokinetic Analysis

The pharmacokinetic analysis was conducted by Covance CRU usingWinNonlin Professional Version 5.2 (Pharsight Corporation, MountainView, Calif., USA). Pharmacokinetic parameters were determined from theplasma concentrations of itraconazole and hydroxyitraconazole usingnon-compartmental procedures.

The pharmacokinetic parameters determined are presented in Table 1.

For the assessment of relative bioavailability, SUBA®-itraconazole(itraconazole) capsules (50 mg under fed and fasted conditions) were thetest formulation and SPORANOX® (itraconazole) capsules (100 mg under fedand fasted conditions) were the reference formulation. Statisticalanalyses were performed separately for the fed and fasted conditions andwere repeated for hydroxyitraconazole. As the variance for allpharmacokinetic parameters increases as the mean increases, thepharmacokinetic parameters AUC0-tlast, AUC0-∞ and Cmax werelog-transformed (base e) prior to analysis and were analyzed using amixed model. The model included sequence, period and treatment as fixedeffects and subject within sequence as a random effect. The leastsquares (LS) means were calculated for these pharmacokinetic parametersfor the test and reference investigational products. Mean differencesbetween the test and reference investigational products were calculated.The residual variance from the mixed model was used to calculate 90% and95% confidence intervals (CIs) for the difference between the test andreference investigational products. These values were back-transformedto give geometric LS means, a point estimate and 90% and 95% CIs for theratio of the test relative to the reference investigational product.This procedure was equivalent to Schuirmann's two one-sided tests at the0.05 level of significance. The parameter tmax was analyzednonparametrically using the Wilcoxon signed-rank test. The mediandifference between the test and reference treatments and thecorresponding 90% and 95% CIs were calculated.

Food Effect

The food assessment was tested separately for the itraconazoleformulations and was repeated for hydroxyitraconazole. Thepharmacokinetic parameters AUC0-tlast, AUC0-∞ and Cmax werelog-transformed (base e) prior to analysis and were analyzed using amixed model. The model included sequence, period and treatment as fixedeffects, and subject with sequence as a random effect. For thesepharmacokinetic parameters, LS means were calculated for the fed andfasted conditions. Mean differences between the fed and fastedtreatments were calculated. The residual variance from the mixed modelwas used to calculate 90% and 95% CIs for the difference between the fedand fasted conditions. These values were back-transformed to givegeometric LS means, a point estimate and 90% and 95% CIs for the ratioof the fed relative to the fasted condition.

The parameter tmax was analyzed nonparametrically using the Wilcoxonsigned-rank test. The median difference between the dietary conditionsand the corresponding 90% and 95% Cis were calculated.

Pharmacokinetic Results

Plasma concentrations of itraconazole following administration ofLOZANOC and SPORANOX® (itraconazole) formulations in both the fasted andfed conditions are summarized in FIGS. 33 (linear) and 34(log-transformed).

Plasma concentrations of itraconazole following administration ofLOZANOC and SPORANOX® (itraconazole) formulations in the fastedcondition are summarized in FIGS. 35 (linear) and 36 (log-transformed).

Plasma concentrations of itraconazole following administration ofLOZANOC and SPORANOX® (itraconazole) formulations in the fed conditionare summarized in FIGS. 37 (linear) and 38 (log-transformed).

The pharmacokinetic parameters of itraconazole are summarized in Table39.

TABLE 39 Summary of the Pharmacokinetic Parameters for ItraconazoleFollowing Administration of LOZANOC and SPORANOX ® (Itraconazole)Formulations in the Fasted and Fed Conditions Treatments 50 mg 100 mgSUBA ®-itraconazole Sporanox ®-itraconazole capsules capsules Fasted FedFasted Fed Parameters (N = 35) (N = 36) (N = 36) (N =36) AUC_(0-tlast)450   359   733   358   (ng · hr/mL) (56.8) (65.4) (52.6) (102)  AUC_(0-∞) 659^(b)   532^(c)   920^(d)   589^(b)   (ng · hr/mL) (34.7)(46.0) (37.3) (54.4) C_(max) 64.0 33.6 63.8 36.2 (ng/mL) (57.5) (68.9)(62.0) (88.2) t_(max)  2.50  6.00  2.50  5.00 (h) (1.00-5.15)(1.00-12.0) (1.50-5.00) (2.00-8.05 T_(lag)a   0.500  2.50   0.500  1.77(h)  (0-1.50  (0-8.02  (0-1.00 (0.500-4.00  T_(1/2)  24.5^(c)  21.5^(c)24.8  21.8^(e) (h) (35.7) (34.6) (33.2) (49.7) CL/F 1245    1566^(c)  1924    2815^(e)   (mL/min) (35.0) (46.0) (45.5) (51.8) V_(z)/F2637^(c)   2919^(c)   4138    5303^(e)   (L) (36.3) (38.7) (60.5) (53.2)Geometric mean (CV %) data are presented N = Number of subjects studied^(a)Median (min-max) ^(b)N = 25, ^(c)N = 26, ^(d)N = 34, ^(e)N = 28

Following the oral administration of each of the LOZANOC (50 mg) andSPORANOX® (100 mg) formulations in the fasted condition, itraconazolewas rapidly absorbed, appearing in plasma at 0.5 hours afteradministration. Maximum plasma concentrations were attained at mediantmax of 2.5 hours post dose, with values for individual subjects rangingfrom 1.0 to 5.2 hours and 1.5 to 5.0 hours post-dose, respectively.After reaching Cmax, plasma concentrations declined in an apparentbiphasic manner, with the start of the elimination phase generallyoccurring at 10 to 24 hours post dose for both formulations and a meanapparent elimination half-life of 25 hours (range in individual subjectsfrom 13.8 to 67.4 hours and 9.3 to 46.2 hours for the LOZANOC andSPORANOX® formulations, respectively). The statistical comparison ofrelative bioavailability of itraconazole in the fasted condition issummarized in Table 40.

TABLE 40 Statistical Comparison of the Relative Bioavailability ofItraconazole Following Administration of 50 mg LOZANOC and 100 mgSPORANOX ® (Itraconazole) in the Fasted Condition Geometric LS mean 50mg SUBA ®- 100 mg Sporanox ®- Ratio of geometric LS means itraconazoleitraconazole SUBA ®: Sporanox ® Parameters (fasted) capsules (90% CI)AUC_(0-tlast) 448 733 0.611 (0.557, 0.670) (ng · hr/mL) AUC_(0-∞) 591866 0.682 (0.629, 0.740) (ng · hr/mL) C_(max) 63.4 63.8 0.993 (0.859,1.15)  (ng/mL) t_(max) ^(a) 2.5 2.5     0 (−.500, 0.258) (h) ^(a) Mediandifference (SUBA ®- itraconazole − Sporanox ® [itraconazole])

In the fasted condition, systemic exposure to itraconazole, based uponAUC0-tlast and AUC0-∞, was lower (by approximately 32 to 39%) whenadministered as the LOZANOC formulation (50 mg) compared to theSPORANOX® formulation (100 mg). Maximum plasma concentrations weresimilar and rapidly attained at median tmax of 2.5 hours post dose forboth formulations. The between-subject variability (geometric CV %,) washigh and generally similar for both formulations in the fastedcondition, ranging from 35% and 37% for AUC0-∞ and 58% and 62% for Cmax.The magnitude of difference in the maximum and minimum exposure betweenindividual subjects was similar for both formulations in terms of AUC0-∞(3.8- and 3.6-fold for the SPORANOX® compared to the SUBA® formulation),however for Cmax, the SPORANOX® formulation was markedly higher thanLOZANOC (17.3- and 8.8-fold, respectively). The statistical comparisonof relative bioavailability of itraconazole in the fed condition issummarized in Table 41.

TABLE 41 Statistical Comparison of Relative Bioavailability ofItraconazole Following Administration of 50 mg LOZANOC and 100 mgSPORANOX ® (Itraconazole) in the Fed Condition Geometric LS mean 50 mgSUBA ®- 100 mg Sporanox ®- Ratio of geometric LS means itraconazoleitraconazole SUBA ®:Sporanox ® Parameters (fed) (fed) (90% CI)AUC_(0-tlast) 359 358  1.00 (0.827, 1.22) (ng · hr/mL) AUC_(0-∞) 521 5910.883 (0.774, 1.05) (ng · hr/mL) C_(max) 33.6 36.2 0.927 (0.763, 1.12)(ng/mL) t_(max) ^(a) 6 5  1.98 (0.500, 2.75) (h) ^(a)Median difference(SUBA^( ®)- itraconazole − Sporanox ® [itraconazole])

Statistical analysis showed itraconazole systemic exposure (based on AUCand Cmax) to be similar between the 2 formulations when administered inthe fed condition. In addition, median tmax for the LOZANOC andSPORANOX® formulations was similar (occurring at 6 and 5 hours,respectively). Higher between-subject variability (geometric CV %) inAUC0-∞ and Cmax occurred in the fed condition compared to the fasted forboth formulations. The magnitude of difference in the maximum andminimum exposure between individual subjects in the fed condition washigher for the LOZANOC formulation than observed in the fasted conditionbeing 5.8- and 18.2-fold for AUC0-∞ and Cmax, respectively. For theSPORANOX® formulation, the differences observed between individualsubjects were 5.8-fold for AUC0-∞ and 20.3-fold for Cmax. Thestatistical comparison of relative bioavailability of itraconazoleadministered as 50 mg LOZANOC in the fasted condition and 100 mgSPORANOX® in the fed condition is summarized in Table 42.

TABLE 42 Statistical Comparison of the Relative Bioavailability ofItraconazole Following Administration of 50 mg LOZANOC in the FastedCondition and 100 mg SPORANOX ® (Itraconazole) in the Fed ConditionGeometric LS mean 50 mg SUBA ®- 100 mg Sporanox ®- Ratio of geometric LSmeans itraconazole itraconazole SUBA ®:Sporanox ® Parameters (fasted)(fed) (90% CI) AUC_(0-tlast) 451 358 1.26 (1.03, 1.54) (ng · hr/mL)AUC_(0-∞) 650 593  1.10 (0.925, 1.30) (ng · hr/mL) C_(max) 63.6 36.21.76 (1.44, 2.14) (ng/mL) t_(max) ^(a) 2.5 5  −2.50 (−3.00, −1.98) (h)^(a)Median difference (SUBA ®- itraconazole fasted −Sporanox ®[itraconazole] fed)

Systemic exposure to itraconazole, based upon AUC0-∞, was similar forthe SUBA® formulation (50 mg) given in the fasted condition and theSPORANOX® formulation (100 mg) given in the fed condition. Statisticalanalysis showed Cmax to be higher for the LOZANOC formulation withmedian tmax occurring more rapidly compared to the SPORANOX®formulation. The between-subject variability (geometric CV %) Table 42for itraconazole was lower when given as the LOZANOC formulation in thefasted condition compared to the SPORANOX® formulation in the fedcondition, being 35% and 54% for AUC0-∞ and 58% and 88% for Cmax,respectively. The magnitude of difference in the maximum and minimumexposure between individual subjects was also lower for the LOZANOCformulation, being 3.8- and 8.8-fold for AUC0-∞ and Cmax, respectively,compared to 5.8- and 20.3-fold, respectively, for the SPORANOX®formulation.

Effect of Dietary Condition on Itraconazole Exposure

The statistical assessment of the effect of dietary condition on thepharmacokinetics of itraconazole is summarized in Table 43 and Table 44.

TABLE 43 Statistical Comparison of the Effect of Dietary Condition onItraconazole Exposure Following Administration of 50 mg LOZANOC in theFed and Fasted Conditions Geometric LS mean Ratio of geometric LS means50 mg SUBA ®-itraconazole capsules Fed:Fasted Parameters Fed Fasted (90%CI) AUC_(0-tlast) 359 454 0.792 (0.718, 0.873) (ng · hr/mL) AUC_(0-∞)524 649 0.808 (0.734, 0.891) (ng · hr/mL) C_(max) 33.6 63.9 0.525(0.446, 0.618) (ng/mL) t_(max) ^(a) 6 2.5 4.23 (3.00, 5.00)  (h)^(a)Median difference (fed − fasted)

TABLE 44 Statistical Comparison of the Effect of Dietary Condition onItraconazole Exposure Following Administration of 100 mg SPORANOX ®(Itraconazole) in the Fed and Fasted Conditions Geometric LS mean 100 mgSporanox ®- Ratio of geometric itraconazole capsules LS means Fed:FastedParameters Fed Fasted (90% CI) AUC_(0-tlast) 358 733 0.488 (0.405,0.587) (ng · h/mL) AUC_(0-∞) 567 866 0.654 (0.568, 0.754) (ng · h/mL)C_(max) 36.2 63.8 0.568 (0.474, 0.681) (ng/mL) t_(max) ^(a) 5 2.5 2.25(1.75, 2.75)  (h)

Statistical assessment showed AUC0-tlast, AUC0-∞ and Cmax foritraconazole to be lower for both formulations when administered in thefed compared to the fasted condition. The effect of food appeared moremarked for the SPORANOX® formulation compared to the LOZANOCformulation, with AUC0-∞ being 35% and 19% lower, respectively, in thefed condition. Cmax was similar for both formulations in the fedcondition and ranged from 43% to 48% lower than the fasted condition.

Plasma concentrations of hydroxyitraconazole following administration ofthe LOZANOC and SPORANOX® (itraconazole) formulations in both the fastedand fed conditions are summarized in FIGS. 39 (linear) and 40(log-transformed).

Plasma concentrations of hydroxyitraconazole following administration ofthe LOZANOC and SPORANOX® (itraconazole) formulations in the fastedconditions are summarized in FIGS. 41 (linear) and 42 (log-transformed).

Plasma concentrations of hydroxyitraconazole following administration ofthe LOZANOC and SPORANOX® (itraconazole) formulations in the fedconditions are summarized in FIGS. 43 (linear) and 44 (log-transformed).

The pharmacokinetic parameters for hydroxyitraconazole are summarized inTable 45.

The metabolite hydroxyitraconazole was rapidly formed followingadministration of both the LOZANOC (50 mg) and SPORANOX® (100 mg)formulations in the fasted condition, with quantifiable levels in plasmabeing observed 0.5 hours after dosing. Maximum plasma concentrations ofhydroxyitraconazole occurred at a median tmax of 3 to 4 hours for bothformulations, with values ranging from 1.5 to 6 hours post dose inindividual subjects). After reaching Cmax, plasma concentrations ofhydroxyitraconazole appeared to decline in an apparent mono-phasicmanner, with the start of the elimination phase generally ranging from2.0 to 6.0 hours post dose for the LOZANOC formulation and 3.0 to 12.0hours post dose for the SPORANOX® formulation. The mean apparentelimination half-life for hydroxyitraconazole was 6.4 and 10.0 hours forthe LOZANOC and SPORANOX® formulations, respectively, with valuesranging from 3.1 to 15.6 hours and 5.8 to 18.6 hours, respectively, inindividual subjects. Systemic exposure to hydroxyitraconazole was higherthan the parent drug following the administration of itraconazole asboth the LOZANOC and SPORANOX® formulations. The extent of formation ofthe metabolite was similar for both formulations in the fed and fastedconditions as shown by the mean metabolic ratios with MRAUC ranging from2.4 to 2.5 and MRCmax ranging from 2.0 to 2.1.

The statistical comparison of relative bioavailability ofhydroxyitraconazole in the fasted condition is summarized in Table 46.

TABLE 45 Summary of the Pharmacokinetic Parameters forHydroxyitraconazole Following Administration of the LOZANOC andSPORANOX ® (Itraconazole) Formulations in the Fasted and Fed ConditionsTreatments 50 mg 100 mg SUBA ®-itraconazole Sporanox ®-itraconazolecapsules capsules Fasted Fed Fasted Fed Parameters (N = 35) (N = 36) (N= 36) (N = 36) AUC_(0-tlast) 1132 868   1802 890 (ng · h/mL) (45.5)(49.1) (50.2) (77.5) AUC_(0-∞) 1163 938^(b)   1875 931 (ng · h/mL)(44.7) (46.2) (47.6) (74.4) C_(max) 129 71.2 137 76.7 (ng/mL) (31.1)(43.2) (42.0) (56.1) t_(max) 3.00  8.00 4.00 6.00 (h) (1.50-5.15)(1.50-12.0) (2.00-6.02) (2.00-10.0 T_(lag) ^(a) 0.500  1.50 0.500 1.50(h)   (0-1.00   (0-8.02   (0-1.00 (0.500-4.00  T_(1/2) 644  71.5^(b)10.0 6.92 (h) (34.7) (27.7) (27.8) (28.8) MR_(AUC) 2.51  2.42 2.46 2.49(20.2) (24.7) (17.6) (30.1) MR_(Cmax) 2.01  2.12 2.14 2.12 (31.5) (29.8)(29.2) (38.9) Geometric mean (CV %) data are presented N = Number ofsubjects studied ^(a)Median (min-max) ^(b)N = 34

TABLE 46 Statistical Comparison of Relative Bioavailability ofHydroxyitraconazole Following Administration of 50 mg LOZANOC and 100 mgSPORANOX ® (Itraconazole) in the Fasted Condition Geometric LS mean 50mg 100 mg Ratio of SUBA ®- Sporanox ® geometric LS means itraconazole(itraconazole) SUBA ®:Sporanox ® Parameters Fed Fasted (90% CI)AUC_(0-tlast) 1127 1802 0.625 (0.569, 0.687) (ng · h/mL) AUC_(0-∞) 11581875 0.618 (0.567, 0.673) (ng · h/mL) C_(max) 128 137 0.935 (0.847,1.03)  (ng/mL) t_(max) ^(a) 3 4 −0.508 (−1.00, −0.233) (h) ^(a) Mediandifference (SUBA ®- itraconazole − Sporanox ® [itraconazole])

As for the parent drug, the extent of exposure to hydroxyitraconazolewas lower (by up to 38% for AUC) when itraconazole was administered asthe LOZANOC formulation compared to the SPORANOX® formulation. Maximumplasma concentrations were similar for both formulations and wereattained at a median of 3 and 4 hours post dose for the LOZANOC andSPORANOX® formulations, respectively. The between-subject variability(geometric CV %, Table 47) was high for both formulations in the fastedcondition and was generally similar, ranging from 45% to 48% for AUC0-∞and 31% to 42% for Cmax. Differences in AUC0-∞ and Cmax of 5.5- and3.9-fold for the LOZANOC formulation and 7.8- and 6.3-fold for theSPORANOX® formulation were observed in the maximum and minimum exposurefor individual subjects.

Systemic exposure (based on AUC and Cmax) to hydroxyitraconazolemirrored that of the parent drug and was similar for both formulationswhen administered in the fed condition, with greater between-subjectvariability (geometric CV %) compared to the fasted condition alsoobserved. The statistical comparison of the relative bioavailability ofhydroxyitraconazole administered as 50 mg LOZANOC in the fastedcondition and SPORANOX® in the fed condition is summarized in Table 48.

TABLE 47 Statistical Comparison of the Relative Bioavailability ofHydroxyitraconazole Following Administration of 50 mg LOZANOC and 100 mgSPORANOX ® (Itraconazole) in the Fed Condition Geometric LS mean Ratioof 50 mg 100 mg geometric LS means SUBA ®- Sporanox ® SUBA ®:Sporanox ®Parameters itraconazole (itraconazole) (90% CI) AUC_(0-tlast) 868 8900.975 (0.809, 1.18) (ng · h/mL) AUC_(0-∞) 941 931  1.01 (0.838, 1.22)(ng · h/mL) C_(max) 71.2 76.7 0.928 (0.791, 1.09) (ng/mL) t_(max) ^(a) 86  1.99 (0.975, 2.50) (h) ^(a)Median difference (SUBA ®- itraconazole −Sporanox ® [itraconazole])

TABLE 48 Statistical Comparison of Relative Bioavailability ofHydroxyitraconazole Following Administration of 50 mg LOZANOC in theFasted Condition and 100 mg SPORANOX ® (Itraconazole) in the FedCondition Geometric LS mean Ratio of 50 mg 100 mg geometric LS meansSUBA ®- Sporanox ® SUBA ®:Sporanox ® Parameters itraconazole(itraconazole) (90% CI) AUC_(0-tlast) 1127 890 1.27 (1.07, 1.50) (ng ·h/mL) AUC_(0-∞) 1159 931 1.24 (1.06, 1.46) (ng · h/mL) C_(max) 128 76.71.67 (1.44, 1.93) (ng/mL) t_(max) ^(a) 3 6  −2.75 (−3.25, −2.25) (h)^(a)Median difference (SUBA ®- itraconazole − Sporanox ® [itraconazole]fed)

Statistical assessment showed that systemic exposure, based uponAUC0-tlast, AUC0-∞ and Cmax for hydroxyitraconazole, was higher for theLOZANOC formulation (fasted) compared to the SPORANOX® formulation(fed). Median tmax occurred earlier for the SUBA® formulation (fasted)compared to the SPORANOX® formulation (fed). As for the parent drug, thebetween-subject variability (geometric CV %, Table 46) forhydroxyitraconazole was similar for each formulation and was generallyhigher when administered in the fed compared to the fasted condition.The magnitude of differences in the maximum and minimum exposure forindividual subjects was lower for the LOZANOC formulation (fasted)compared to the SPORANOX® formulation (fed) i.e. 5.5- and 3.9-fold forAUC0-∞ and Cmax and 12.5- and 8.3-fold, respectively.

Effect of Dietary Condition on Hydroxyitraconazole Exposure

The statistical assessment of the effect of dietary condition on thepharmacokinetics of hydroxyitraconazole is summarized in Table 49 andTable 50.

As for the parent drug, statistical assessment showed AUC0-tlast, AUC0-∞and Cmax for hydroxyitraconazole to be lower for each formulation whenadministered in the fed compared to the fasted condition. The effect offood appeared more marked for the SPORANOX® formulation compared to theLOZANOC formulation.

TABLE 49 Statistical Comparison of the Effect of Dietary Condition onHydroxyitraconazole Exposure Following Administration of 50 mg LOZANOCin the Fed and Fasted Conditions Geometric LS mean Ratio of 50 mgSUBA ®-itraconazole geometric LS means capsules Fed:Fasted ParametersFed Fasted (90% CI) AUC_(0-tlast) 868 1136 0.764 (0.705, 0.829) (ng ·h/mL) AUC_(0-∞) 929 1170 0.794 (0.733, 0.861) (ng · h/mL) C_(max) 71.2129 0.553 (0.493, 0.622) (ng/mL) t_(max) ^(a) 8 3 4.50 (3.50, 5.49)  (h)^(a)Median difference (fed − fasted)

TABLE 50 Statistical Comparison of the Effect of Dietary Condition onHydroxyitraconazole Exposure Following Administration of 100 mgSPORANOX ® (Itraconazole) in the Fed and Fasted Conditions Geometric LSmean Ratio of 100 mg Sporanox ®-itraconazole geometric LS means capsulesFed:Fasted Parameters Fed Fasted (90% CI) AUC_(0-tlast) 890 1802 0.494(0.425, 0.574) (ng · h/mL) AUC_(0-∞) 931 1875 0.497 (0.428, 0.576) (ng ·h/mL) C_(max) 76.7 137 0.561 (0.494, 0.636) (ng/mL) t_(max) ^(a) 6 42.01 (1.51, 2.75)  (h) ^(a)Median difference (fed − fasted)

Between-subject variability was high for itraconazole AUC and Cmax forboth formulations. Higher variability was noted in the fed compared tothe fasted condition and also for the SPORANOX® compared to the LOZANOCformulation.

Administration of itraconazole as the 50 mg LOZANOC formulation in thefasted condition provided similar overall exposure (AUC0-∞) compared tothe 100 mg SPORANOX® formulation in the fed condition with approximately1.8-fold higher Cmax and lower between-subject variability.

The pharmacokinetics of hydroxyitraconazole reflected those of theparent drug following administration of the LOZANOC and SPORANOX®formulations in the fed and fasted conditions.

Analysis of Adverse Events

Headache was the most frequently reported drug-related adverse event. Atotal of 7 episodes were reported by 4 subjects, with 3 of thesesubjects reporting headache in at least 2 treatment periods. One subjectexperienced single episodes of mild to moderate headache following 100mg SPORANOX® in both the fed and fasted conditions; one subjectexperienced single episodes of mild headache following 50 mg LOZANOC inboth the fed and fasted conditions; one subject experienced a singleepisode of moderate headache following 50 mg LOZANOC (fasted) andSubject 23 experienced single episodes of mild to moderate headachefollowing 50 mg LOZANOC (fasted) and 100 mg SPORANOX® (fasted). Episodesof headache occurred between approximately 2 hours and 6 days post doseand lasted between approximately 3 hours and 7 days. All 4 subjectsrequired concomitant medication (paracetamol) for the treatment ofheadache.

Fatigue was the second most frequently reported drug-related adverseevent, with single episodes reported by 4 subjects (2 subjects following50 mg LOZANOC [fed] and 2 subjects following 100 mg SPORANOX® [fasted]).All episodes of fatigue were mild in severity and resolved withouttreatment, occurring between 33 minutes and 5 hours post dose andlasting from 30 minutes to approximately 23 hours. The only otherdrug-related adverse event reported by 2 subjects was rash following 50mg LOZANOC in the fed condition. All other drug-related adverse eventswere single episodes only and included lethargy, abdominal pain,diarrhea and dry lips.

Discussion

This study investigated the relative bioavailability of itraconazolewhen administered as 50 mg LOZANOC and 100 mg SPORANOX® (itraconazole)capsule formulations in both the fed and fasted conditions. Theadministration of itraconazole as the 50 mg LOZANOC formulation comparedto the clinically used 100 mg SPORANOX® formulation in the fastedcondition was found to provide similar maximum plasma concentrations,however systemic exposure (based upon AUC) was lower overall. In the fedcondition, exposure to itraconazole was lower than observed in thefasted condition for both formulations and, although food appeared tohave a greater impact on the SPORANOX® formulation compared to theLOZANOC formulation, AUC0-∞ and Cmax were similar for both formulations.

The between-subject variability for AUC and Cmax was also high for bothitraconazole formulations, being greater in the fed compared to thefasted condition, as was the magnitude of difference in the maximum andminimum exposure for individual subjects. Higher between-subjectvariability, however, was noted for the SPORANOX® compared to theLOZANOC formulation in the fed condition.

Administration of the LOZANOC formulation in the fasted condition wasshown to have advantages over the SPORANOX® formulation in the fedcondition regarding itraconazole exposure. The LOZANOC formulationprovided a more rapidly attained and higher Cmax (1.8-fold higher),similar AUC0-∞, and lower between-subject variability for administrationof half the required itraconazole dose (50 mg vs. 100 mg).

Single oral doses of itraconazole as 50 mg LOZANOC and 100 mg SPORANOX®formulations were safe and well tolerated by healthy male and femalesubjects in this study. Both adverse events observed during this studywere not considered to be drug-related. There were no severe adverseevents reported for the study. The overall incidence of drug-relatedadverse events was low and slightly higher for the LOZANOC formulationcompared to the SPORANOX® formulation in both the fed and fastedconditions, respectively.

Between-subject variability was noted for itraconazole AUC and Cmax forboth formulations. Higher variability was noted in the fed compared tothe fasted condition and also for the SPORANOX® compared to the LOZANOCformulation.

Administration of itraconazole as the 50 mg LOZANOC formulation in thefasted condition provided similar overall exposure (AUC0-∞) compared tothe 100 mg SPORANOX® formulation in the fed condition with approximately1.8-fold higher Cmax and lower between-subject variability.

The pharmacokinetics of hydroxyitraconazole reflected those of theparent drug following administration of the LOZANOC and SPORANOX®formulations in the fed and fasted conditions.

Single oral doses of itraconazole administered as the 50 mg LOZANOC and100 mg SPORANOX® formulations were considered to be safe and welltolerated when administered to healthy male and female subjects in thefed and fasted conditions in this study.

Example 11—Variability Analysis of the Studies Described in Examples 10and 9

The main purpose of the studies conducted was to assess bioequivalenceof 50 mg capsules of the oral solid dosage form of the present inventionwith SPORANOX® 100 mg capsules. However, we also assessed the data fromthe two SPORANOX® 100 mg capsules administrations for “bioequivalence”to itself. The results of this analysis are shown in Table 51.

TABLE 51 “Bioequivalence” analysis of SPORANOX ® 100 mg capsules firstand second occurrence AUC Ratio C_(max) Ratio Sporanox 0.802 0.792(0.654-0.984) (0.848-0.989)

The AUC data show that the ratio of means fell just within 80-125% butthe lower boundary of the 90% confidence interval was at only 65.4% ofnominal. Furthermore, the upper boundary of the AUC ratio did notinclude 1.00. The Cmax data were similar (ratio of means very close 5 to80%; lower boundary of 90% CI at 64.8%; upper boundary of 90% CI below1.00). The data shows a difference in bioavailability betweenconsecutive SPORANOX® 100 mg capsule administrations. This demonstratesthat the bioavailability of itraconazole from SPORANOX® 100 mg capsulesis subject to wide variation, even when dosed on separate occasions inthe same subject population.

The outcome of the corresponding analysis for the oral solid dosage formof the present invention in the form of 50 mg capsules is shown in Table52. The ratio of AUC means is close to unity and the 90% CI falls within80-125%. For Cmax, the intra-subject CV % for both administrations was33.3% and so the lower boundary of the required 90% CI for the ratio ofmeans will fall slightly below 0.80.

TABLE 52 “Bioequivalence” analysis of SUBACAP ™ 50 mg capsules first andsecond occurrence AUC Ratio C_(max) Ratio SUBACAP 0.985 0.901(0.811-1.110) (0.778-1.04)

It is known that the absorption of itraconazole from SPORANOX® 100 mgcapsules is highly variable. By reducing the variability prescribers canbe more confident of the exposure obtained by each patient. It istherefore relevant, when comparing 50 mg capsules of the oral soliddosage form of the present invention and SPORANOX® 100 mg capsules, touse clinical pharmacology data to understand:

-   -   1) The probability that a patient receiving a 50 mg capsule oral        solid dosage form of the present invention will achieve a lower        exposure than is necessary for therapeutic effect, compared to        the corresponding probability with SPORANOX® 100 mg capsules.    -   2) The probability that a patient receiving a 50 mg capsule oral        solid dosage form of the present invention will achieve a much        greater exposure than is necessary compared to the corresponding        probability with SPORANOX® 100 mg capsules.

In order to assess the performance of 50 mg capsules of the oral soliddosage form of the present invention in this way the data was analyzedat the individual level. Accordingly, the following analyses, all basedon AUC0-∞ following single administration in the fed state, arepresented below:

Analysis of median, range and inter-quartile range (IQR) for Study 1(Example 9) and Study 2 (Example 10).

-   -   1) Comparative graphs of AUC values in Study 1.    -   2) Comparative graphs of AUC values in Study 2.    -   3) Box plots and Bartlett's tests (to investigate differences in        variability between formulations).    -   4) Ratio of AUC0-∞ to minimum inhibitory concentration (AUC/MIC)        data 5 for Study 1 and Study 2.

AUC0-∞ was selected for the above analyses based on recommendations byMoulton et al (Mouton, Dudley et al. 2005). Data were excluded in caseswhere AUC0-∞ required >30% extrapolation from AUC(0-t last).

For all Box-plots presented, height of box and whiskers indicatevariability of AUC. Box-plots show: lower hinge=25% quantile,middle=median (50% quantile), upper hinge=75% quantile. Lowerwhisker=lower hinge−1.5×interquartile range (IQR), and upperwhisker=upper hinge+1.5×IQR. Outliers outside the lower and upperwhiskers are shown as points.

The Bartlett's test (Snedecor and Cochran, (1989), Statistical Methods,Eighth Edition, Iowa State University Press) is used to test if ksamples have equal variances. Bartlett's test is sensitive to departuresfrom normality. The Bartlett's test examines the hypothesis that twodistributions have different variability (e.g. as characterized bystandard deviation) regardless of mean or median value of thedistribution. A p-value of 0.05 was used as the cut-off for statisticalsignificance. The Bartlett's test outcome is presented under eachBox-plot, with a comparison of the results presented in Table 53.

Study 1

The median, IQR and range of 50 mg capsule oral solid dosage forms ofthe present invention and SPORANOX® 100 mg Capsules AUC0-∞ in Study 1are shown in Table 53. The corresponding Box-plots are presented inFIGS. 45-47.

TABLE 53 Analysis of median, IQR and range in Study 1 AUC_(0-∞) (ng ·h/ml) 50 mg capsule oral solid dosage forms of the present inventionSporanox FED & FED & Parameter FASTED FED FASTED FASTED FED FASTEDNumber of data points N = 25 N = 26 N = 50 N = 33 N = 28 N = 58 Median699 515 632 868 527 765 IQR 534-812 681 472-755 701-1168 423-922608-1092 Q₃-Q₁ 278 297 284 467 499 483 Range 336-1267 249-1435 249-1435576-2101 216-1254 216-2101

The Bartlett's test of homogeneity of variances for untransformed AUCgave a p-value of 0.002, which indicates that the variance wassignificantly different between the two formulations when the results ofeach formulation with and without food are pooled. It is apparent fromFIG. 45 that the 50 mg capsule oral solid dosage form of the presentinvention has a less variable AUC0-∞ than the SPORANOX® 100 mg capsuleformulation.

It is apparent from the Box-plot of FIG. 46 that the 50 mg capsule oralsolid dosage form of the present invention is less variable with respectto AUC0-∞ than the SPORANOX® 100 mg capsule formulation in the fedstate.

It is apparent from the Box-plot of FIG. 47 that the 50 mg capsule oralsolid dosage form of the present invention in the fasted state is lessvariable than the Sporanox® 100 mg capsule formulation in the fed state.

It is apparent from FIG. 48 that the 50 mg capsule oral solid dosageform of the present invention is less variable than the SPORANOX® 100 mgcapsule formulation, both in the fasted state. The Bartlett's test ofhomogeneity of variances for untransformed AUC gave a p-value of 0.006,which indicates that the variance was significantly different betweenthe two formulations in the fasted state.

Study 2

The median, IQR and range of 50 mg capsule oral solid dosage forms ofthe present invention and SPORANOX® 100 mg capsules AUC0-∞ in Study 2are shown in Table 54. Corresponding Box-plot analyses are shown inFIGS. 49 and 50.

TABLE 54 Analysis of median, IQR and range in Study 2 (fed only)AUC_(0-∞) (ng · h/ml) 50 mg capsule oral solid dosage Parameter forms ofthe present invention Sporanox First administration Number of datapoints N = 32 N = 38 Median 505 765 IQR 416-882  456-1155 Q₃-Q₁ 466 699Range 299-1981 239-1816 Second administration Number of data points N =35 N = 38 Median 596 922 IQR 463-935  656-1211 Q₃-Q₁ 472 555 Range267-1723 269-6026

The Bartlett's test of homogeneity of variances for untransformed AUCgave a p-value of <0.001, which indicates that the variance wassignificantly different between the two formulations when the resultsfrom each occurrence are pooled. FIG. 49 shows that the 50 mg capsuleoral solid dosage form of the present invention is less variable thanthe SPORANOX® 100 mg capsule formulation.

The Bartlett's test of homogeneity of variances for untransformed AUCgave a p-value of <0.001, which indicates that the variance issignificantly different between the two formulations for the secondoccurrence. FIG. 50 shows that the 50 mg capsule oral solid dosage formof the present invention is less variable than the SPORANOX® 100 mgcapsule formulation, with two high outlying observations in theSPORANOX® 100 mg capsule group.

The fact that Study 2 was of replicate design also allowed investigationof the within-patient variability between two separate administrations.The modulus (|m|) of the difference between the two AUC0-∞ values wascalculated for each data pair. These datasets were then used to assessthe within-subject variability of 50 mg capsule oral solid dosage formof the present invention as compared to SPORANOX® 100 mg capsuleformulation (Table 55). The greater within-subject variabilityassociated with Sporanox is easily visualized when the ranked modulusvalues are plotted according to magnitude (FIG. 51). Note that FIG. 51excludes an outlier SPORANOX® 100 mg capsule formulation modulus valueof 4934 ng·h/ml. Thus, it can be concluded that there is a dramaticdifference in favor of the oral solid dosage form of the presentinvention regarding the within-subject reproducibility of dosing.

As mentioned, the Bartlett's test examines the hypothesis that twodistributions have different variability (e.g. as characterized bystandard deviation) regardless of mean or median value of thedistribution. A p-value of 0.05 was used as the cut-off for statisticalsignificance. Table 56 summarizes the Bartlett's test results from theAUC distribution analyses on Studies 1 and 2.

TABLE 55 Within subject variability of AUC0-∞ in Study 2 - 50 mg capsuleoral solid dosage form of the present invention versus SPORANOX ® 100 mgcapsules Within-Subject Variation in AUC_((0-∞) (ng · hr/ml) 50 mgcapsule oral solid dosage forms of the present Parameter inventionSporanox Number of replicate values N = 28 N = 31 Σ|m| 4141 18091Arithmetic mean 147.9 583.6 Geometric mean 60.5 320.8 Median 77 337 IQR16-258 132-585 Range  1-624  33-4934 Bartlett's test result P < 0.001

TABLE 56 Summary of Bartlett's test Results - Study 1 and 2 STUDYCOMPARISON p-VALUE 1 50 mg capsule oral solid dosage forms of thepresent 0.002* invention vs Sporanox - fed and fasted pooled 50 mgcapsule oral solid dosage forms of the present 0.494 invention vsSporanox - fed state only 50 mg capsule oral solid dosage forms of thepresent 0.087 invention vs Sporanox - fasted state only 50 mg capsuleoral solid dosage forms of the present 0.006* invention fasted vsSporanox fed 2 50 mg capsule oral solid dosage forms of the present<0.001* invention vs Sporanox - both occurances pooled 50 mg capsuleoral solid dosage forms of the present 0.660 invention vs Sporanox -1^(st) occurance 50 mg capsule oral solid dosage forms of the present<0.001* invention vs Sporanox - 2^(nd) occurance *Statiscallysignificant as p < 0.05

The following conclusions can be made from review of Table 56:

1) In Study 1, the variance in AUC0-∞ for the 50 mg capsule oral soliddosage form of the present invention is significantly lower thanSPORANOX® 100 mg capsules when the fed and fasted data are pooled, whichin part is due to the variance being significantly less when the 50 mgcapsule oral solid dosage form of the present invention is taken in thefasted state versus SPORANOX® 100 mg capsules in the fed state.

2) In Study 2, the variance in AUC0-∞ for the 50 mg capsule oral soliddosage form of the present invention is significantly lower thanSPORANOX® 100 mg capsules due to the “second occurrence” effect that wasobserved for SPORANOX® 100 mg capsules but not for the 50 mg capsuleoral solid dosage form of the present invention.

Thus, one would expect that the exposure following administration of a50 mg capsule oral solid dosage form of the present invention can bemore reliably predicted than for SPORANOX® 100 mg capsules, regardlessof whether taken in the fed or the fasted state.

It may be noted that the Box-plot analyses also indicate that less drugis delivered from a 50 mg capsule oral solid dosage form of the presentinvention than a SPORANOX® 100 mg capsule. However, this observation isconsistent with bioequivalence analyses conducted from Study 1 and Study2 (Table 57), where in the fed state the AUC(0-72 h) exposure from 50 mgcapsule oral solid dosage forms of the present invention wasbioequivalent in Study 1 and more than 20% lower in Study 2.

TABLE 57 Relative bioavailability of 50 mg capsules of the oral soliddosage form of the present invention and SPORANOX ® 100 mg capsules inStudies 1 and 2 AUC_((0-72 h)) ratio (SUBACAP/Sporanox) STUDY Foodstatus (90% CI) 1 Fed 1.00 (0.827, 1.22) Fasted 0.611 (0.557, 0.670) 2Fed 0.774 (0.696, 0.861)

Apart from the Box-plots, another way of looking at the raw AUC0-∞ datais to rank them according to size and plot them. FIG. 52 shows thatexposure to 50 mg capsule oral solid dosage forms of the presentinvention and SPORANOX® 100 mg capsules is essentially the same for the50% of subjects who absorb the least drug.

There is a slightly greater exposure to SPORANOX®100 mg capsules in the50% of subjects who absorb the most drug (as would be expected giventhat double the quantity of drug substance is present in SPORANOX® 100mg capsules).

Bioequivalence Study Example 12—Bioequivalence Study Comparing SingleOral Doses of SUBA®-Itraconazole 50 mg Capsules with Sporanox®(Itraconazole) 100 mg Capsules Under Fed Conditions

Study Rationale

This study was performed to determine the bioequivalence of LOZANOC(SUBA®-itraconazole) and SPORANOX®. Due to enhanced bioavailability, a50 mg dose of SUBA®-itraconazole has been shown to result in similarexposure to itraconazole as observed following a 100 mg dose ofSPORANOX® with lower inter- and intra-subject variability. Due to theknown high intra-subject variability of the reference product(SPORANOX®), this study will assess the bioequivalence of the twoproducts (i.e. a 50 mg dose of LOZANOC compared to a 100 mg dose ofSPORANOX®) using a replicate two-treatment, four-period, two-sequencestudy design. In addition, the study will be conducted under fedconditions since it is known that the bioavailability of itraconazoleapproximately doubles when administered with food.

This study was an open-label, analytically-blinded investigation as themain objectives were based on pharmacokinetic parameters, which are notbelieved to be subject to bias. A crossover design was chosen tominimize the effect of between-subject variability. The subjects wererandomized such that an equal number of subjects received the treatmentsin the same order in each of the two sequences. As the SPORANOX®itraconazole is considered to be a highly variable drug product; thestudy was conducted as a replicate cross-over design to assess thewithin-subject variability of the maximum observed plasma concentration(Cmax) of the SPORANOX® itraconazole. If intra-variability of Cmax wasfound to be greater than 30% the acceptance criteria for bioequivalencecould be widened. In each treatment period, blood sampling up to 120hours post dose allowed the pharmacokinetic parameters of itraconazoleand hydroxyitraconazole to be adequately described, based on theexpected apparent plasma terminal elimination half-life (t½) foritraconazole and hydroxyitraconazole of 22 hours and 7 hours,respectively. A washout period of 14 days was chosen for this study, asthis was deemed to be an appropriate amount of time to guarantee thatthe dose of itraconazole administered in the previous treatment periodwill have cleared from the subjects' bloodstream prior to thecommencement of the next treatment period.

Study Design

This was a 2 treatment, 4-period, 2-sequence, single dose, cross-over,randomized, replicate-design bioequivalence study in healthy male andfemale subjects. Forty-eight (48) subjects participated in the study.Screening was performed in the 28-day period prior to the first dose.There was a minimum of 14 days between each dose administration.Subjects had post-study visit assessments performed at their Day 6 visitin Treatment Period 4.

Study Treatments

Test Formulation: capsules containing 50 mg itraconazole (LOZANOC).

Reference Formulation: 100 mg capsules SPORANOX® (itraconazole)

In each treatment period subjects received one of the following 2treatments:

Treatment A: 1×50 mg LOZANOC capsule administered following a high-fatbreakfast.

Treatment B: 1×100 mg LOZANOC capsule administered following a high-fatbreakfast.

Each subject received Treatment A in 2 treatment periods and Treatment Bin 2 treatment periods in accordance with a randomization schedule.

Blood samples were collected pre-dose and at the following times afteradministration of each dose: 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8,10, 12, 24, 36, 48, 72, 96 and 120 hours post dose Following collection,The samples were centrifuged, within 1 hour of collection, at 1500 g for10 minutes at approximately 4° C. The serum was stored at −20° C.

Sample Analysis

The analysis of itraconazole and hydroxyitraconazole in plasma sampleswas performed by the Department of Bioanalytical Services at CovanceLaboratories Europe (CLE), Harrogate, UK using a validated analyticalmethod. The plasma samples were prepared by solid phase extraction. Thecentrifuged eluates were quantified by liquid chromatography with tandemmass spectrometric detection (LC-MS/MS).

Pharmacokinetic Analysis

The pharmacokinetic analysis was conducted by Covance CRU usingWinNonlin Professional Version 5.2 (Pharsight Corporation, MountainView, Calif., USA). Pharmacokinetic parameters were determined from theplasma concentrations of itraconazole and hydroxyitraconazole usingnon-compartmental procedures.

The pharmacokinetic parameters determined are presented in Table 1.

For the assessment of bioequivalence 50 mg SUBA® itraconazole was thetest formulation and 100 mg SPORANOX® was the reference formulation.Statistical analysis was performed separately for itraconazole andhydroxyitraconazole. The pharmacokinetic parameters AUC0-72 h,AUC0-tlast, AUC0-∞, and Cmax were log-transformed and analyzed using arepeated measures, linear mixed-effects model where formulation, periodand sequence were considered as fixed factors, and subject as a randomeffect. From the model, the difference in least squares (LS) meanestimates and the corresponding 90% confidence intervals (CIs) for thedifference were estimated and back-transformed from the log scale toprovide estimates of the ratio of geometric means and 90% CI for theratio of these means.

If the 90% CI for treatment ratios (test/reference) for AUC0-72 h wascontained within 0.80 to 1.25 for itraconazole, then the formulationscould be considered bioequivalent. As the reference formulation isconsidered to be a highly variable drug product, the 90% CIbioequivalence acceptance range for Cmax was widened. The extent ofwidening was based on the calculated within-subject variability (CV %)for Cmax. The widened Cmax lower and upper limits permitted according tothe European Medicines Agency (EMEA) Guidance7 are displayed in Table58.

TABLE 58 Confidence Interval Acceptance range Within-subject CV (%)Lower Limit Upper Limit 30 80.00 125.00 35 77.23 129.48 40 74.62 134.0245 72.15 138.59 ≥50 69.84 143.19

Residual plots were produced to assess the adequacy of the model. Themodel was used to investigate the within- and between-subjectvariability for each treatment.

Pharmacokinetic Analysis

Single Oral Dose Pharmacokinetics of Itraconazole FollowingAdministration of Two Different Formulations (SUBA®-Itraconazole andSPORANOX® [Itraconazole]) in the Fed Condition on Two Dosing OccasionsEach

Plasma concentrations of itraconazole following administration of theSUBA®-itraconazole and SPORANOX® (itraconazole) formulations in the fedcondition on two dosing occasions each are summarized in FIGS. 53(linear) and 54 (log-transformed).

The pharmacokinetic parameters of itraconazole are summarized in Table59.

Following the oral administration of each of the SUBA® (50 mg) andSPORANOX® (100 mg) formulations in the fed condition, itraconazole wassteadily absorbed, appearing in plasma at 1.0 hour after administration.Median tmax for the SUBA® and SPORANOX® formulations was similar(occurring at 5.50 and 5.00 hours, respectively), with values forindividual subjects ranging from 1.0 to 24.0 hours and 1.0 to 10.0 hourspost-dose, respectively. Mean maximum plasma concentrations were lowerfor the SUBA® formulation than for the SPORANOX®, being 41.4 ng/mL and52.8 ng/mL, respectively. After reaching Cmax, plasma concentrationsdeclined in an apparent biphasic manner, with the start of theelimination phase generally occurring at 12 to 24 hours post dose forboth formulations and a mean t1/2 of 20.2 and 23.9 hours (range inindividual subjects from 9.57 to 46.4 hours and 10.8 to 45.7 hours) forthe SUBA® and SPORANOX® formulations, respectively.

In general, as assessed from the geometric CV %, high between-subjectvariability was noted for AUC0-72 h, AUC0-tlast, AUC0-∞ and Cmax foreach of the formulations. However, between-subject variability in totalexposure was consistently lower for the SUBA® formulation than theSporanox® with respective values of 41.8% and 59.8% for AUC0-72 h, 57.7%and 84.7% for AUC0-tlast, and 51.3% and 67.0% for AUC0-∞.Between-subject variability in Cmax was similar for the SUBA® and theSPORANOX® formulations (59.8% and 65.2%, respectively).

Statistical analysis of occurrence on the pharmacokinetic parameters ofitraconazole is summarized in Table 60.

TABLE 59 Summary of the Pharmacokinetic Parameters for ItraconazoleFollowing Administration of the SUBA ®-itraconazole and SPORANOX ®(Itraconazole) Formulations in Fed Condition Treatment 50 mg SUBA ®capsule fed 100 mg Sporanox ® capsule fed Occurrence OccurrenceOccurrence Occurrence Parameters 1 2 Average 1 2 Average AUC_(0-72 h)547 (42.3) 556 (41.9) 552 (41.8) 637 (52.4) 794 (64.7) 712 (59.8) (ng ·h/mL) N 40 41 81 39 40 79 AUC_(0-tlast) 465 (60.7) 496 (55.0) 480 (57.7)535 (81.4) 683 (86.1) 604 (84.7) (ng · h/mL) N 47 47 94 47 47 94AUC_(0-∞) 608 (52.8) 625 (50.8) 616 (51.3) 733 (61.8) 919 (70.2) 822(67.0) (ng · h/mL) N 32 34 66 37 38 75 C_(max) 39.3 (63.0) 43.6 (56.6)41.4 (59.8) 47.0 (61.2) 59.3 (67.1) 52.8 (65.2) (ng/mL) N 47 47 94 47 4794 t_(max) ^(a) (h) 5.50 (2.00-12.0) 5.50 (1.00-24.0) 5.50 (1.00-24.0)5.00 (1.00-10.0) 5.00 (1.00-10.0) 5.00 (1.00-10.0) N 47 47 94 47 47 94T_(lag) ^(a) (h) 2.00 (0-8.00) 1.00 (0-8.00) 2.00 (0-8.00) 1.00 (0-4.00)1.00 (0-4.02) 1.00 (0-4.02) N 47 47 94 47 47 94 T_(1/2)(h) 20.2 (37.6)20.2 (41.9) 20.2 (39.5) 23.3 (47.6) 24.5 (40.5) 23.9 (43.9) N 32 34 6637 38 75 CL/F 1371 (52.8) 1334 (50.8) 1352 (51.3) 2275 (61.8) 1813(70.2) 2028 (67.0) (mL/min) N 32 34 66 37 38 75 V_(z)/F (L) 2400 (30.6)2332 (29.8) 2365 (30.0) 4598 (37.5) 3845 (54.3) 4200 (47.3) N 32 34 6637 38 75 Geometric mean (CV %) data are presented. N = Number ofsubjects studied, AUC_(0-72 h) = Area under the plasmaconcentration-time curve from time zero up to 72 hours postdose,AUC_(0-tlast) = Area under the plasma concentration-time curve from timezero up to the last quantifiable concentration, AUC_(0-∞) = Area underthe plasma concentration-time curve from time zero to infinity, C_(max)= Maximum observed plasma concentration, t_(max) = Time of maximumobserved plasma concentration, t_(lag) = Time before the start ofabsorption, t_(1/2) = Apparent plasma terminal elimination half-life,CL/F = Apparent total plasma clearance, V_(z)/F = Apparent volume ofdistribution during the terminal phase. ^(a)Median (min-max).

TABLE 60 Occurrence Analysis of the Pharmacokinetic Parameters ofItraconazole Geometric LS mean Ratio (occurrence Occur- Occur-1:Occurrence 2) Parameter Treatment rence 1 rence 2 (90% CI)AUC_(0-72 h) 50 mg 539 546 0.987 (0.914, 1.07)  (ng · h/mL) SUBA ®capsule fed 100 mg 615 780 0.789 (0.672, 0.925) Sporanox ® capsule fedAUC_(0-tlast) 50 mg 464 496 0.936 (0.851, 1.03)  (ng · h/mL) SUBA ®capsule fed 100 mg 533 680 0.784 (0.665, 0.925) Sporanox ® capsule fedAUC_(0-∞) 50 mg 593 631 0.939 (0.854, 1.03)  (ng · h/mL) SUBA ® capsulefed 100 mg 703 911 0.771 (0.645, 0.921) Sporanox ® capsule fed C_(max)50 mg 39.2 43.5 0.902 (0.807, 1.01)  (ng/mL) SUBA ® capsule fed 100 mg46.8 59.1 0.792 (0.704, 0.891) Sporanox ® capsule fed AUC_(0-72 h) =Area under the plasma concentration-time curve from time zero up to 72hours postdose, AUC_(0-tlast) = Area under the plasma concentraton-timecurve from time zero up to the last quantifiable concentration,AUC_(0-oo) = Area under the plasma concentration-time curve from timezero to infinity, C_(max) = Maximum observed plasma concentration, LS =least squares.

Statistical analysis showed that the systemic exposure (based on AUC andCmax) from the 50 mg SUBA® formulation was less variable between dosingoccurrences than that of the SPORANOX® (FIG. 55). The ratios ofgeometric LS means for the SUBA® formulation were close to unity(ranging from 0.902 to 0.987); whereas the ratios for the SPORANOX® wereconsiderably lower (ranging from 0.771 to 0.792) due to the higherexposure seen in Occurrence 2. A review of individual subject profilesfound 2 subjects (Subject 27 and Subject 42) with outlying results. Theincreased exposure and variability between dosing occurrences with 100mg SPORANOX® can be partially explained by these values (Table 61).

The statistical analysis of bioequivalence for itraconazole in the fedcondition is summarized in Table 62.

TABLE 61 Pharmacokinetic Parameters for Outlying Subjects FollowingDosing with 100 mg SPORANOX ® Subject 27 Subject 42 Parameter Occurrence1 Occurrence 2 Occurrence 1 Occurrence 2 AUC_(0-72 h) 1209 2449 904 4842(ng · h/mL) AUC_(0-tlast) 1389 2883 980 5601 (ng · h/mL) AUC_(0-∞) 15193232 1092 6026 (ng · h/mL) C_(max) 108 171 83.4 329 (ng/mL) AUC_(0-72 h)= Area under the plasma concentration-time curve from time zero up to 72hours postdose, AUC_(0-tlast) = Area under the plasma concentraton-timecurve from time zero up to the last quantifiable concentration,AUC_(0-oo) = Area under the plasma concentration-time curve from timezero to infinity, C_(max) = Maximum observed plasma concentration.

TABLE 62 Bioequivalence Analysis of the Pharmacokinetic Parameters ofItraconazole Following Administration of 50 mg SUBA ®-itraconazole and100 mg SPORANOX ® (Itraconazole) in the Fed Condition Geometric LS meanRatio (50 mg SUBA ® Within-subject CV % (90% CI) 50 mg 100 mg capsulefed:100 50 mg 100 mg SUBA ® Sporanox ® mg Sporanox ® SUBA ® Sporanox ®Parameter capsule fed capsule fed capsule fed (90% CI) capsule fedcapsule fed AUC_(0-72 h) 536 692 0.774 (0.696, 0.861) 20.9 (17.4, 26.3)44.8 (36.9, 57.6) (ng · h/mL) AUC_(0-tlast) 479 602 0.797 (0.704, 0.901)27.8 (23.6, 34.0) 51.2 (43.1, 63.7) (ng · h/mL) AUC_(0-∞) 611 800 0.763(0.678, 0.859) 22.2 (18.1, 29.3) 47.4 (38.7, 62.1) (ng · h/mL) C_(max)41.3 52.6 0.785 (0.695, 0.888) 33.3 (28.3, 40.9) 35.5 (30.1, 43.5)(ng/mL) AUC_(0-72 h) = Area under the plasma concentration-time curvefrom time zero up to 72 hours postdose, AUC_(0-tlast) = Area under theplasma concentraton-time curve from time zero up to the lastquantifiable concentration, AUC_(0-oo) = Area under the plasmaconcentration-time curve from time zero to infinity, C_(max) = Maximumobserved plasma concentration.

Statistical analysis of the systemic exposure results (based on AUC andCmax) showed that the 50 mg SUBA® capsule was not bioequivalent with the100 mg SPORANOX® capsule with respect to itraconazole. For the measuresof AUC, the ratio of the geometric means ranged from 0.763 to 0.797,with none of the associated 90% CI for the geometric LS mean ratiosfully contained within the predefined equivalence limits of 0.80 to1.25. For Cmax, the ratio of geometric LS mean ratios was 0.785 andwithin-subject CV % for the SUBA® and the SPORANOX® formulation was33.3% and 35.5%, respectively. Therefore, using the expanded 0.746 to1.340 equivalence range allowed, based on the reference formulation andwithin-subject CV %, bioequivalence can not be concluded for Cmax.

Within-subject variability in total exposure was considerably lower forthe SUBA® formulation than for the SPORANOX® with values of 20.9% and44.8% for AUC0-72 h, 27.8% and 51.2% for AUC0-tlast and 22.2% and 47.4%for AUC0-∞, respectively. There was no overlap in the 90% confidenceinterval ranges obtained for the 2 formulations at each AUC measure.Therefore the difference in within-subject variability was statisticallysignificant at the 90% level.

Within-subject variability in Cmax was similar for the SUBA® and theSPORANOX® formulations (33.3% and 35.5%, respectively).

Single Oral Dose Pharmacokinetics of Hydroxyitraconazole FollowingAdministration of Two Different Formulations (SUBA®-Itraconazole andSPORANOX® [Itraconazole]) in the Fed Condition on Two Dosing OccasionsEach

Plasma concentrations of hydroxyitraconazole following administration ofthe SUBA®-itraconazole and SPORANOX® (itraconazole) formulations in thefed condition on two dosing occasions each are summarized in FIG. 56(linear) and FIG. 57 (log-transformed).

The pharmacokinetic parameters of hydroxyitraconazole are summarized inTable 63.

TABLE 63 Summary of the Pharmacokinetic Parameters forHydroxyitraconazole Following Administration of the SUBA ®-itraconazoleand SPORANOX ® (Itraconazole) Formulations in Fed Condition Treatments50 mg SUBA ® capsule fed 100 mg Sporanox ® capsule fed OccurrenceOccurrence Occurrence Occurrence Parameters 1 2 Average 1 2 AverageAUC_(0-72 h) 1089 (54.2) 1159 (49.3) 1123 (51.6) 1212 (72.8) 1492 (82.2)1345 (78.1) (ng · h/mL) N 46 45 91 47 47 94 AUC_(0-tlast) 1025 (59.2)1073 (54.9) 1049 (56.8) 1173 (75.8) 1455 (85.6) 1307 (81.4) (ng · h/mL)N 47 47 94 47 47 94 AUC_(0-∞) 1098 (55.5) 1169 (50.1) 1133 (52.6) 1223(73.9) 1509 (84.2) 1358 (79.7) (ng · h/mL) N 46 45 91 47 47 94 C_(max)(ng/mL) 78.7 (36.3) 82.6 (35.8) 80.6 (35.9) 90.3 (43.1) 106 (50.2) 97.8(47.3) N 47 47 94 47 47 94 t_(max) ^(a)(h) 6.50 6.50 6.50 5.50 5.00 5.50(2.00-24.3) (2.00-24.0) (2.00-24.3) (2.00-10.0) (2.00-10.0) (2.00-10.0)N 47 47 94 47 47 94 t_(lag) ^(a) (h) 1.00 1.00 1.00 1.00 1.00 1.00(0-7.00) (0-5.50) (0-7.00) (0-4.00) (0-3.52) (0-4.00) N 47 47 94 47 4794 t_(1/2) (h) 7.99 (32.8) 8.16 (29.7) 8.07 (31.1) 8.25 (34.6) 8.54(35.1) 8.40 (34.7) N 32 34 66 37 38 75 MR_(AUC) 2.00 (17.4) 1.97 (17.4)1.98 (17.2) 1.97 (16.7) 1.95 (17.2) 1.96 (16.8) N 32 34 66 37 38 75MR_(Cmax) 2.00 (32.3) 1.90 (28.9) 1.95 (30.6) 1.92 (28.0) 1.78 (26.6)1.85 (27.4) N 47 47 94 47 47 94 Geometric mean (CV %) data arepresented. N = Number of subjects studied, AUC_(0-72 h) = Area under theplasma concentration-time curve from time zero up to 72 hours postdose,AUC_(0-tlast) = Area under the plasma concentration-time curve from timezero up to the last quantifiable concentration, AUC_(0-∞) = Area underthe plasma concentration-time curve from time zero to infinity, C_(max)= Maximum observed plasma concentration, t_(max) = Time of maximumobserved plasma concentration, t_(lag) = Time before the start ofabsorption, t_(1/2) = Apparent plasma terminal elimination half-life,MR_(AUC) = Metabolic ratio based on AUC, MR_(Cmax) = Metabolic ratiobased on C_(max). ^(a)Median (min-max).

Following the oral administration of each of the SUBA® (50 mg) andSPORANOX® (100 mg) formulations in the fed condition,hydroxyitraconazole was steadily formed, appearing in formulations wassimilar (occurring at 6.50 and 5.50 hours, respectively), with valuesfor individual subjects ranging from 2.0 to 24.3 hours and 2.0 to 10.0hours post-dose, respectively. Mean maximum plasma concentrations werelower for the SUBA® formulation than for the SPORANOX®, being 80.6 ng/mLand 97.8 ng/mL, respectively. After reaching Cmax, plasma concentrationsof hydroxyitraconazole declined in an apparent mono-phasic manner, withthe start of the elimination phase generally occurring at 8 to 12 hourspost dose for both formulations and a mean t1/2 of 8.07 and 8.40 hours(range in individual subjects from 4.59 to 19.2 hours and 4.15 to 21.5hours) for the SUBA® and SPORANOX® formulations, respectively. Systemicexposure to hydroxyitraconazole was higher than the parent drugfollowing the administration of itraconazole as both the SUBA® andSPORANOX® formulations. The extent of formation of the metabolite wassimilar for both formulations as shown by the mean metabolic ratios withMRAUC ranging from 1.95 to 2.0 and MRCmax ranging from 1.78 to 2.0.

In general, as assessed from the geometric CV %, high between-subjectvariability was noted for AUC0-72 h, AUC0-tlast and AUC0-00, withmoderate between-subject variability in Cmax for the SUBA® formulation.The between-subject variability in exposure was lower for the SUBA®formulation than for the SPORANOX® with values of 51.6% and 78.1% forAUC0-72 h, 56.8% and 81.4% for AUC0-tlast, 52.6% and 79.7% for AUC0-∞,and 35.9% and 47.3% for Cmax, respectively.

Statistical analysis of occurrence on the pharmacokinetic parameters ofhydroxyitraconazole is summarized in Table 64.

As observed with itraconazole pharmacokinetic parameters, Subjects 27and 42 again showed outlying results in AUC measures for dosingOccurrence 2.

The statistical analysis of bioequivalence for hydroxyitraconazole inthe fed condition is summarized in Table 65.

TABLE 64 Occurrence Analysis of the Pharmacokinetic Parameters ofHydroxyitraconazole Geometric LS mean Ratio (occurrence ParameterTreatment Occurrence 1 Occurrence 2 1:Occurrence 2) (90% CI)AUC_(0-72 h) 50 mg SUBA ® capsule fed 1085 1144 0.949 (0.867, 1.04)  (ng· h/mL) 100 mg Sporanox ® capsule fed 1206 1485 0.813 (0.704, 0.938)AUC_(0-tlast) 50 mg SUBA ® capsule fed 1022 1071 0.954 (0.873, 1.04) (ng · h/mL) 100 mg Sporanox ® capsule fed 1167 1448 0.806 (0.695, 0.935)AUC_(0-∞) 50 mg SUBA ® capsule fed 1094 1153 0.949 (0.868, 1.04)  (ng ·h/mL) 100 mg Sporanox ® capsule fed 1217 1501 0.811 (0.701, 0.938)C_(max) 50 mg SUBA ® capsule fed 78.5 82.4 0.952 (0.876, 1.04)  (ng/mL)100 mg Sporanox ® capsule fed 90.1 105 0.854 (0.767, 0.951) AUC_(0-72 h)= Area under the plasma concentration-time curve from time zero up to 72hours postdose, AUC_(0-tlast) = Area under the plasma concentraton-timecurve from time zero up to the last quantifiable concentration,AUC_(0-oo) = Area under the plasma concentration-time curve from timezero to infinity, C_(max) = Maximum observed plasma concentration, LS =least squares.

TABLE 65 Bioequivalence Analysis of the Pharmacokinetic Parameters ofHydroxyitraconazole Following Administration of 50 mgSUBA ®-itraconazole and 100 mg SPORANOX ® (Itraconazole) in the FedCondition Geometric LS mean Ratio (50 mg SUBA ® Within-subject CV % (90%CI) 50 mg 100 mg capsule fed:100 50 mg 100 mg SUBA ® Sporanox ® mgSporanox ® SUBA ® Sporanox ® Parameter capsule fed capsule fed capsulefed (90% CI) capsule fed capsule fed AUC_(0-72 h) 1108 1338 0.828(0.737, 0.929) 25.8 (21.9, 31.7) 44.0 (37.2, 54.4) (ng · h/mL)AUC_(0-tlast) 1046 1300 0.805 (0.716, 0.905) 26.1 (22.2, 31.9) 45.7(38.6, 56.6) (ng · h/mL) AUC_(0-∞) 1117 1352 0.826 (0.736, 0.927) 25.9(22.0, 31.8) 44.5 (37.6, 55.0) (ng · h/mL) C_(max) 80.4 97.5 0.825(0.754, 0.904) 24.7 (21.0, 30.1) 32.1 (27.3, 39.3) (ng/mL) AUC_(0-72 h)= Area under the plasma concentration-time curve from time zero up to 72hours postdose, AUC_(0-tlast) = Area under the plasma concentraton-timecurve from time zero up to the last quantifiable concentration,AUC_(0-oo) = Area under the plasma concentration-time curve from timezero to infinity, C_(max) = Maximum observed plasma concentration

Statistical analysis of the systemic exposure to hydroxyitraconazole(based on AUC and Cmax) for the 50 mg SUBA® capsule was lower than thatwith the 100 mg SPORANOX® capsule. For the measures of AUC, the ratio ofthe geometric means ranged from 0.805 to 0.828, with the associated 90%CIs excluding unity. Similarly for Cmax, the ratio of the geometricmeans was 0.825, and the associated 90% CIs excluded unity.

Within-subject variability in total exposure was considerably lower forthe SUBA® formulation than for the SPORANOX® with values of 25.8% and44.0% for AUC0-72 h, 26.1% and 45.7% for AUC0-tlast, and 25.9% and 44.5%for AUC0-∞, respectively. There was no overlap in the 90% confidenceinterval ranges obtained for the 2 formulations at each AUC measure.Therefore the difference in within-subject variability was statisticallysignificant at the 90% level.

Within subject variability for Cmax was lower for the SUBA® formulationthan for the SPORANOX® with values of 24.7% and 32.1%, respectively.However, this difference was not statistically significant at the 90%level.

The systemic exposure to itraconazole, based upon AUC and Cmax, was 20%to 24% lower when administered as the SUBA® itraconazole formulationcompared to the SPORANOX® formulation in the fed condition (AUC0-72 h,536 nigh/mL and 692 ng·h/mL; AUC0-tlast, 479 ng·h/mL and 602 ng·h/mL;AUC0-∞, 611 ng·h/mL and 800 ng·h/mL; and Cmax, 41.3 ng/mL and 52.6ng·h/mL, respectively).

Between-subject variability was noted for itraconazole AUC and Cmax forboth formulations. However, between-subject variability in totalexposure was consistently lower for the SUBA® formulation compared tothe SPORANOX® formulation.

Systemic exposure for the SUBA® formulation was considerably lessvariable between dosing occurrences than that of the 100 mg SPORANOX®.

Within-subject variability in total exposure to itraconazole wasstatistically significantly lower for the SUBA® formulation compared tothe SPORANOX® at the 90% level. Within-subject variability in Cmax wassimilar for both formulations.

The pharmacokinetics of hydroxyitraconazole reflected those of theparent drug following administration of the SUBA® and SPORANOX®formulations in the fed condition.

Adverse Events

Single oral doses of itraconazole, administered as the 50 mgSUBA®-itraconazole and 100 mg SPORANOX® (itraconazole) formulations,were well tolerated by male and female subjects when given in the fedcondition. There were no serious adverse events and no severe adverseevents reported during the study.

The majority of adverse events reported during the study were notrelated to treatment with the study drug. The incidence of drug-relatedadverse events (the number of subjects reporting adverse events) wasslightly lower following 50 mg SUBA®-itraconazole. The number ofdrug-related adverse events was slightly higher following 50 mgSUBA®-itraconazole compared to 100 mg SPORANOX®. The majority ofdrug-related adverse events were mild in severity and resolved withouttreatment.

Discussion

This study investigated the bioequivalence of itraconazole whenadministered as 50 mg SUBA®-itraconazole and 100 mg SPORANOX®(itraconazole) capsule formulations in the fed condition. The presentstudy was conducted using a replicate design, which is justified giventhe highly variable pharmacokinetics of itraconazole.

The administration of itraconazole as the 50 mg SUBA® formulationcompared to the clinically used 100 mg SPORANOX® formulation in thefasted condition was found to provide 20% to 24% lower systemic exposure(AUC0-72 h, 536 ng·h/mL and 692 ng·h/mL; AUC0-tlast, 479 ng·h/mL and 602ng·h/mL; and AUC0-∞, 611 ng·h/mL and 800 ng·h/mL, respectively) and 21%lower maximum plasma concentrations (41.3 ng/mL and 52.6 ng·h/mL,respectively). Statistical analysis of the systemic exposure results(based on AUC and Cmax) showed that the 50 mg SUBA® capsule formulationwas not bioequivalent with the 100 mg SPORANOX® capsule. This result isin contrast to a previous bioavailability study (Example 10) whichdemonstrated that SUBA®-itraconazole 50 mg capsules under fed conditionscompared to SPORANOX® 100 mg capsules under fed conditions met thebioequivalence criteria for highly variable drugs. However, the resultsof the study demonstrated that the SUBA® formulation was less variablein pharmacokinetic profile than the SPORANOX®.

Although between-subject variability was high for all measures ofsystemic exposure to itraconazole with both formulations of the studydrug, the SUBA® formulation demonstrated consistently lowerbetween-subject variability than the SPORANOX®. Between-subjectvariability in Cmax was similar for the SUBA® and the SPORANOX®formulations.

Statistical analysis showed that the systemic exposure with the SUBA®formulation was also less variable between dosing occurrences. Ratios ofgeometric LS means (Occurrence 1: Occurrence 2) for the SUBA®formulation were close to unity (range of 0.902 to 0.987); whereas theratios for the SPORANOX® were considerably lower (range from 0.771 to0.792).

The increase in exposure and between-subject variability followingdosing with 100 mg SPORANOX® can be partially explained by 2 subjectswith outlying pharmacokinetic data. Subject 27 and Subject 42 displayedsignificant increases in exposure in Occurrence 2 compared toOccurrence 1. For Subject 27, AUC measures increased by approximatelydouble and Cmax increased 1.6-fold. Subject 42 showed particularly highvariability, AUC measures increased approximately 5.5-fold and Cmaxincreased 4-fold between Occurrence 1 and Occurrence 2. No reasons couldbe found for this increased exposure following dosing with the 100 mgSPORANOX® capsules.

Within-subject variability in total exposure was considerably lower(approximately 50%) for the SUBA® formulation than for the SPORANOX®.Analysis of the confidence intervals obtained for AUC0-72 h, AUC0-tlastand AUC0-∞ for the two formulations showed no overlap of the ranges. Onthis basis, it was concluded that the lower within-subject variabilityobserved for the SUBA® formulation was statistically significant at the90% level compared to the SPORANOX®. Within-subject variability in Cmaxwas similar for the SUBA® and the Sporanox® formulations.

Single oral doses of itraconazole as 50 mg SUBA® and 100 mg SPORANOX®formulations were safe and well tolerated by healthy male and femalesubjects in this study. The majority of adverse events reported duringthe study were not related to treatment with the study drug. There wereno serious adverse events, no severe adverse events reported during thestudy and the majority of drug-related adverse events were mild inseverity and resolved without treatment. Headache was the mostfrequently reported drug-related adverse event. A total of 17 episodeswere reported by 12 subjects, with 4 of these subjects reportingheadache in at least 2 treatment periods. Overall, the incidence andfrequency of headaches were similar for both treatments.

There were no clinically significant findings in clinical laboratoryevaluations, vital signs, ECGs and physical examination findings duringthe study.

The systemic exposure to itraconazole, based upon AUC and Cmax, was 20%to 24% lower when administered as the SUBA® itraconazole formulationcompared to the SPORANOX® formulation in the fed condition (AUC0-72 h,536 ng·b/mL and 692 ng·h/mL; AUC0-tlast, 479 ng·h/mL and 602 ng·b/mL;AUC0-00, 611 ng·h/mL and 800 ng·h/mL; and Cmax, 41.3 ng/mL and 52.6ng·h/mL, respectively).

Between-subject variability was noted for itraconazole AUC and Cmax forboth formulations. However, between-subject variability in totalexposure was consistently lower for the SUBA® formulation compared tothe SPORANOX® formulation.

Systemic exposure for the SUBA® formulation was considerably lessvariable between dosing occurrences than that of the 100 mg SPORANOX®.

Within-subject variability in total exposure to itraconazole wasstatistically significantly lower for the SUBA® formulation compared tothe SPORANOX® at the 90% level. Within-subject variability in Cmax wassimilar for both formulations.

The pharmacokinetics of hydroxyitraconazole reflected those of theparent drug following administration of the SUBA® and SPORANOX®formulations in the fed condition.

There were no clinically significant findings in clinical laboratoryevaluations, vital signs, ECGs and physical examination findings duringthe study.

Single oral doses of itraconazole administered as the 50 mg SUBA® and100 mg SPORANOX® formulations were considered to be safe and welltolerated when administered to healthy male and female subjects in thefed condition in this study.

Re-Analysis of this Study's Dataset

Although not pre-defined in the study protocol, Applicants conductedre-analysis of the dataset in order to better understand the resultsobtained. Specifically, Applicants explored two issues:

-   -   1. Applicants noted that the European Medicines Agency        guidelines outline different statistical methodologies that can        be used to analyze data from replicate-design pharmacokinetic        studies.    -   2. Noting that subject 27 and 42 displayed significant increases        in exposure following administration of the Reference in        Occurrence 2 compared to Occurrence 1 but not after        administration of the Test, Applicants investigated the affect        on the bioequivalence comparisons if these subjects were removed        from the analysis.

There are three possible methods by which to analyze the data from thisstudy:

-   -   1) “Approach compatible with CHMP guideline (Method A)”, which        is the same analysis method as is used for 2×2 trials.    -   2) “Slight modification to approach compatible with CHMP        guideline (Method B)”    -   3) An alternative method outlined in FDA guidance (Method C).

Initially, Applicants were of the view that the FDA method, Method C,was the optimal approach and it was used when analyzing the results fromthis study. Post-completion of this study however, Applicants'interpretation is that Method A is a preferred method when the sourcesof variation are thought to be fixed rather than random effects, andthat Method C is acceptable when the sources of variation are thought tobe random rather than fixed effects but tends to provide widerconfidence intervals than Method A.

Given the results of this study used Method C, Applicants commissionedanalysis of the data using Method A.

As subject 42 demonstrated the greatest increase in exposure followingReference Occurrence 2, it was decided to investigate the effect ofremoving this subject from the bioequivalence analyses.

Below are qualitative summaries of the bioequivalence ratios andconfidence intervals derived using the existing SAP (Method C) (Table66), and Method A (Table 67); a “yes” value indicates that theacceptance criteria are met, a “no” value indicates that the acceptancecriteria have not been met. Table 68, Table 69 and Table 70 providequantitative summaries.

A review of the qualitative summary under the current SAP, Method C,presented in (Table 66) indicates that there are several permutationsfor which the ratio for either Cmax or AUC0-72 meets the acceptancecriteria. Overall, there is no observable trend or pattern. However,none of the permutations yielded an acceptable confidence interval(i.e., 0.80-1.25). As the reference formulation is considered to be ahighly variable drug product, the 90% CI bioequivalence acceptance rangefor Cmax can be widened. The extent of widening is based on thecalculated within-subject variability (CV %) for Cmax. The qualitativesummaries presented in (Table 66) and (Table 67) present thewithin-subject variability that would have to observed in order for theCmax ratio to be acceptable. Aside from the basic analysis, where bothoccurrences are pooled for both the Test and Reference, the withinsubject variability criteria are not met.

A review of the qualitative summary under Method A (Table 67) indicatesthat there are several permutations for which the ratio for either Cmaxor AUC0-72 meets the acceptance criteria. Overall, there is noobservable trend or pattern. However, none of the permutations yieldedan acceptable confidence interval (i.e., 0.80-1.25). Further, the withinsubject variability criteria are not met.

Hence the conclusions from this re-analysis of this study's dataset are:

-   -   1. Using generally accepted statistical methods, 90% confidence        intervals were widened based on Reference within subject        variability.    -   2. In all cases, itraconazole Cmax and AUC values failed on the        lower boundary of the widened 90% confidence intervals.    -   3. In a few cases, the T/R ratios for Cmax and AUC were within        the 80-125% criteria.    -   4. The deletion of data from one subject (subject #42) did not        significantly change the results.

TABLE 66 Qualitative Summary of the Ratios and Confidence Intervals forthe Comparisons Performed, using the Current SAP Approach (Method C)BIOEQUIVALENCE AUC₀₋₇₂ C_(max) CV % Test Reference Ratio CI Ratio CITarget SUBACAP both Sporanox both NO NO NO NO 35% Occurances PooledOccurances Pooled SUBACAP both Sporanox YES NO YES NO 40% OccurancesPooled Occurance 1 only SUBACAP Sporanox YES NO YES NO 45% Occurance 1Occurance 1 only SUBACAP both Sporanox both YES NO YES NO 50% OccurancesPooled Occurances Pooled Minus Subject 42 SUBACAP both Sporanox NO NO NONO 40% Occurances Pooled Occurance 1 only- Minus Subject 42 SUBACAPSporanox YES NO NO NO 50% Occurance 1 Occurance 1 only- Minus Subject 42DRUG PERFORMANCE AUC₀₋₇₂ C_(max) CV % Test Reference Ratio CI Ratio CITarget Difference in Difference in YES NO NO NO 50% Absorption forAbsorption for Sporanox Sporanox Occurance 1 Occurance 2 Difference inDifference in YES NO YES NO 50% Absorption for Absorption for SporanoxSporanox Occurance 1- Occurance 2- Minus Subject 42 Minus Subject 42Difference in Difference in YES YES YES NO 35% Absorption for Absorptionfor SUBACAP SUBACAP Occurance 1 Occurance 2 Difference in Difference inYES YES YES NO 35% Absorption for Absorption for SUBACAP SUBACAPOccurance 1- Occurance 2- Minus Subject 42 Minus Subject 42

TABLE 67 Qualitative Summary of the Ratios and Confidence Intervals forthe Comparisons Performed, using the EMA Approach, Method ABIOEQUIVALENCE AUC₀₋₇₂ C_(max) CV % Test Reference Ratio CI Ratio CITarget SUBACAP both Sporanox both NO NO NO NO 50% Occurances PooledOccurances Pooled SUBACAP both Sporanox YES NO YES NO 40% OccurancesPooled Occurance 1 only SUBACAP Sporanox YES NO YES NO 40% Occurance 1Occurance 1 SUBACAP both Sporanox both NO NO NO NO 35% OccurancesPooled- Occurances Pooled- Minus Subject 42 Minus Subject 42 SUBACAPboth Sporanox YES NO YES NO 40% Occurances Pooled- Occurances 1 only-Minus Subject 42 Minus Subject 42 SUBACAP Sporanox YES NO YES NO 45%Occurance 1- Occurance 1- Minus Subject 42 Minus Subject 42

TABLE 68 Quantitative Summary of the Geometric LS Means for theComparisons Performed using the Current SAP Approach (Method C)Geometric LS Mean AUC(inf) Cmax AUC(0-72) AUC(last) 50 mg 100 mg 50 mg100 mg 50 mg 100 mg 50 mg 100 mg SUBA Sporanox SUBA Sporanox SUBASporano × SUBA Sporano × Capsule Capsule Capsule Capsule Capsule CapsuleCapsule Capsule Fed Fed Fed Fed Fed Fed Fed Fed Original Analyses 536692 479 602 611 800 41.3 52.6 EXISTING SAP SUBACAP both Occurances 537690 492 599 607 800 41.4 52.4 Pooled vs Sporanox both Occurances PooledSUBACAP both Occurances 538 617 492 561 611 716 41.4 49 Pooled vsSporanox Occurance 1 only SUBACAP Occurance 1 vs 534 616 466 530 593 69739.3 46.7 Sporanox Occurance 1 SUBACAP both Occurances 527 673 480 585594 779 40.6 51.4 Pooled vs Sporanox both Occurances Pooled-MinusSubject 42 SUBACAP both Occurances 526 614 480 556 603 714 40.3 48.9Pooled vs Sporanox Occurance 1 only- Minus Subject 42 SUBACAP Occurance1 vs 521 612 455 526 577 693 38.4 46.3 Sporanox Occurance 1- MinusSubject 42 Difference in Absorption for 637 794 733 919 535 683 46.959.3 Sporanox Occurance 1 vs Occurance 2 Difference in Absorption for630 757 528 652 724 873 46.4 57.1 Sporanox Occurance 1 vs Occurance2-Minus Subject 42 Difference in Absorption for 547 556 464 519 608 62439.3 43.6 SUBACAP Occurance 1 vs Occurance 2 Difference in Absorptionfor 534 543 452 507 589 606 38.3 42.9 SUBACAP Occurance 1 vs Occurance2-Minus Subject 42

TABLE 69 Quantitative Summary of the Geometric LS Means for theComparisons Performed, using the EMEA Approach, Method A Geometric LSMean AUC(0-72) AUC(last) AUC(inf) C_(max) 50 mg 100 mg 50 mg 100 mg 50mg 100 mg 50 mg 100 mg SUBA Sporanox SUBA Sporanox SUBA Sporano × SUBASporano × Capsule Capsule Capsule Capsule Capsule Capsule CapsuleCapsule Fed Fed Fed Fed Fed Fed Fed Fed Original Analyses 536 692 479602 611 800 41.3 52.6 METHOD FROM EMEA GUIDANCE SUBACAP both Occurances537 690 492 600 612 799 41.4 52.5 Pooled vs Sporanox both OccurancesPooled SUBACAP both Occurances 526 618 481 556 603 714 40.6 48.9 Pooledvs Sporanox Occurance 1 only SUBACAP Occurance 1 vs 534 616 466 530 593697 39.3 46.6 Sporanox Occurance 1 SUBACAP both Occurances 527 673 481584 599 778 40.6 51.4 Pooled vs Sporanox both Occurances Pooled-MinusSubject 42 SUBACAP both Occurances 526 614 480 566 603 714 40.3 48.9Pooled vs Sporanox Occurance 1 only-Minus Subject 42 SUBACAP Occurance 1vs 521 612 454 526 577 693 38.4 46.3 Sporanox Occurance 1-Minus Subject42

TABLE 70 Quantitative Summary of the Ratios and Confidence Intervals forthe Comparisons Performed, Current SAP Approach (Method C) Ratio (50 mgSUBA: 100 mg Sporanox) AUC(0-72) AUC(last) AUC(int) Cmax Lower UpperLower Upper Lower Upper Lower Upper 90% 90% 90% 90% 90% 90% 90% 90%Ratio CI CI Ratio CI CI Ratio CI CI Ratio CI CI Original Analysis 0.7740.696 0.861 0.797 0.704 0.901 0.763 0.678 0.859 0.785 0.695 0.888Existing SAP SUBACAP both 0.778 0.700 0.865 0.821 0.723 0.932 0.7600.676 0.855 0.789 0.700 0.865 Occurances Pooled vs Sporanox bothOccurances Pooled SUBACAP both 0.872 0.786 0.966 0.878 0.773 0.997 0.8540.763 0.954 0.843 0.757 0.938 Occurances Pooled vs.Sporanox Occurance 1only SUBACAP 0.867 0.760 0.989 0.897 0.762 1.010 0.850 0.737 0.981 0.8430.730 0.973 Occurance 1 vs Sporanox Occurance l SUBACAP both 0.783 0.7020.873 0.822 0.721 0.936 0.762 0.676 0.868 0.791 0.698 0.896 OccurancesPooled vs. Sporanox both Occurances Pooled-Minus Subject 42 SUBACAP both0.857 0.783 0.938 0.864 0.767 0.974 0.844 0.761 0.937 0.831 0.751 0.920Occurances Pooled vs Sporanox Occurance 1 only-Minus Subject 42 SUBACAPOccurance 0.852 0.748 0.970 0.864 0.749 0.997 0.832 0.724 0.958 0.8310.719 0.960 1 vs Sporanox Occurance 1-Minus Subject 42 Difference in0.802 0.654 0.984 0.797 0.632 0.101 0.784 0.611 0.101 0.792 0.648 0.969Absorption for Sporanox Occurance 1 vs Occurance 2 Difference in 0.8320.717 0.967 0.81 0.671 0.978 0.829 0.699 0.984 0.812 0.698 0.944Absorption for Sporanox Occurance 1 vs. Occurance 2-Minus Subject 42Difference in Absorption 0.985 0.811 1.11 0.895 0.767 1.04 0.974 0.8341.14 0.901 0.778 1.04 for SUBACAP Occurrance 1 vs. Occurance 2Difference in 0.983 0.88 1.1 0.892 0.768 1.04 0.971 0.836 1.13 0.8490.773 1.03 Absorption for SUBACAP Occurrance 1 vs. Occurance 2- MinusSubject 42

Example 13—A Comparison and Analysis Across Bioavailability Studies

Table 71 presents an overview of the biopharmaceutical studies, andTable 71 presents a comparison of the results. A summary of the keyobservations across the studies is presented below.

Rate of Exposure

The rate of exposure to itraconazole after single doses of Test (1×50mg) and of the European Reference (1×100 mg) formulations in the fed andthe fasted states were comparable:

-   -   In the study described in Example 10 the tmax was 6 hours for        the Test and 5 hours for the Reference in the fed state and 2.5        hours for both formulations in the fasted state.    -   In the study described in Example 12 the tmax was 6.5 hours for        the Test and 5.5 hours for the Reference.        Extent of Exposure        Single Dose Studies

The extent of exposure after single doses of Test (1×50 mg) and of theEuropean Reference (1×100 mg) formulations was investigated in twobioequivalence studies: (i) a four-way crossover-design in both the fedand fasted states (Example 10) and (ii) a replicate-designed study inthe fed state (Example 12).

In both studies, 50 mg of the Test itraconazole had an overall exposurethat was comparable to, but lower than the Reference in both the fed andthe fasted states:

-   -   1) In Example 10 in the fed state, the Test met exhibited 90%        confidence intervals and test/reference (T/R) ratios for the        AUC0-t value. In relation to Cmax, the T/R ratio was 0.93,        however, the lower boundary of the 90% confidence internal was        0.76 and therefore did not meet the BE criteria.    -   2) In Example 10 in the fasted state, the T/R ratios were 0.61        and 0.99 for the AUC0-t and Cmax.    -   3) In Example 12 in the fed state, the T/R ratios were 0.80 and        0.79 for the AUC0-t and Cmax, with the lower boundary of the 90%        confidence internal below 0.80 for both parameters.

In Example 10, the exposure to itraconazole was higher for both the Testand the Reference in the fasted compared to the fed state, although thefood effect was less pronounced for the Test than the Reference:

-   -   a) Fasted/fed Ratio of Test: 1.26 and 1.90 for AUC0-t and Cmax,        respectively;    -   b) Fasted/fed Ratio of Reference: 2.05 and 1.76 for AUC0-t and        Cmax, respectively.

In the Single Dose studies with US-sourced Reference the followingobservations can be made:

-   -   a) Dose-proportional bioavailability of the Test at doses of 50        mg, 60 mg and 70 mg for both AUC and Cmax;    -   b) The bioavailability of Itraconazole from a single 100 mg dose        of the Reference is comparable to the bioavailability of        Itraconazole from the 50 mg dose of the Test;    -   c) A single 110 mg dose of the Test is comparable to the        bioavailability of Itraconazole from a 200 mg dose of the        Reference.        Multiple Dose Studies

Consistent with the Single dose studies described above, Multiple dosestudies conducted with US Reference demonstrated that the Test exhibitedan AUC and Cmax that were 20-30% lower for the Test compared to theReference:

-   -   1) Example 6: the overall steady state bioavailability of        itraconazole as measured by AUC and Cmax of a multiple dose of        the Test (2×50 mg capsules) given for 15 consecutive days is        approximately 20% lower than that of a multiple dose of the        Reference (2×100 mg capsules) given for 15 consecutive days        under fed conditions.    -   2) Example 7: the overall steady state bioavailability of        itraconazole as measured by AUC and Cmax of a twice daily dose        of the Test (2×50 mg capsules) given for 14.5 consecutive days        is approximately 30% lower than that of a twice daily dose of        the Reference (2×100 mg capsules) given for 14.5 consecutive        days under fed conditions.        Variation in Exposure        Single Dose Studies

In both Single dose studies involving European-Reference drug, in thefed state the Test formulation demonstrated less variation in exposurethan the Reference, particularly for AUC0-tlast:

-   -   1) Example 12: the Test demonstrated less intra-subject        variation than the Reference, with % CV of 27.8% versus 51.2%        for AUC0-tlast    -   2) Example 10: the Test demonstrated less inter-subject        variation than the Reference, with % CV of 65 versus 102 for        AUC0-tlast and 66 versus 88 for Cmax.

Taking into account the results from Study Example 12, the highervariation in exposure from the Reference is at least partially explainedby a minority of subjects who absorb up to 5-fold higher than the mean.

Multiple Dose Studies—US Sourced Reference

Following twice/day dosing with food, SUBACAP™ 50 mg Hard Capsules (2×50mg) demonstrated less fluctuations at steady state (on day 15) thanUS-sourced SPORANOX® (2×100 mg) (0.1213 vs. 0.2667 and 0.118 vs. 0.29)as determined by both [(Cmax on Day 15−Cmin on Day 15)/Cave on Day 15]and [(Cmax on Day 15−Cmin on Day 15)/Cmin on Day 15].

In addition, standard deviation values for AUC, Cmax, and Cmin weresignificantly lower following dosing with SUBACAP™ 50 mg Hard Capsulescompared with SPORANOX® indicating that the Test product showed lessvariance compared to the Reference product.

However, the results of the once/day dosing in Example 6, showed thatthe fluctuations at steady state (on day 15) for SUBACAP™ 50 mg HardCapsules and SPORANOX® (2×100 mg) were essentially similar using bothmethods of calculation (0.9668 vs. 0.8518 and 1.41 vs. 1.31), withSUBACAP™ 50 mg Hard Capsules actually a little higher. In addition,although the standard deviation values for AUC0-72 h, Cmax, and Cmin,were lower following dosing with SUBA®-Itraconazole compared withSPORANOX®, the difference was not so marked as following the twice/daydosing regimen.

TABLE 71 Overview of SUBACAP ™ 50 mg Capsule Study PK Program Study DoseDose Number n Dates (SUBACAP ™) (Sporanox ®) Fed/Fasted HGN008 48November 2010 1 × 50 mg 1 × 100 mg Fed HGN007 36 March 2010 1 × 50 mg 1× 100 mg Fed and fasting 10850702 24 October 2008 1 × 50 mg, 1 × 100 mgFasted 2 × 50 mg 2 × 100 mg 10850706 24 August 2008 4 × 50 mg 4 × 100 mgFed 10850705 24 August 2008 2 × 50 mg 2 × 100 mg Fed 10850703 36 July2008 1 × 50 mg 1 × 100 mg Fed and fasting CM3007 12 September 2007 1 ×50 mg + 2 × 100 mg Fed and fasting 1 × 60 mg CM2907 12 June 2007 50 mg,60 mg, 1 × 100 mg Fed 70 mg

TABLE 72 Comparison of PK Parameter Results post-IND Studies 1 FastedDose Ranging 10850702 (N = 24) Parameter 1 x SUBA ® 1 x Sporanox ® Ratio90% C.I. AUC_(0-t) 635.81 744.98 0.8535 0.7035-1.0354 AUC_(0-∞) 683.56805.34 0.8488 0.7007-1.0282 C_(max) 70.72 59.45 1.1894 0.9517-1.4865Fasted Dose Ranging 10850702 (N = 24) Parameter 2 x SUBA ® 2 xSporanox ® Ratio 90% C.I. AUC_(0-t) 1674.84 1570.63 1.0664 0.8813-1.2903AUC_(0-∞) 1814.68 1722.77 1.0534 0.8718-1.2727 C_(max) 156.50 122.011.2827 1.0295-1.5982 Fed Fasted 10850703 (N = 36) Parameter SUBA ®Fasted Sporanox ® Fasted Ratio 90% C.I. AUC_(0-t) 676.00 927.60 0.72880.6299-0.8432 AUC_(0-∞) 735.77 1011.63 0.7273 0.6268-0.8440 C_(max)69.92 71.26 0.9813 0.8113-1.1870 Fed Fasted 10850703 (N = 36) ParameterSUBA ®-Fed Sporanox ® Fed Ratio 90% C.I. AUC_(0-t) 533.30 692.62 0.77000.6639-0.8930 AUC_(0-∞) 588.76 762.64 0.7720 0.6656-0.8954 C_(max) 32.7650.11 0.6538 0.5388-0.7934 Fed Fasted 10850703 (N = 36) Parameter SUBA ®Fasted Sporanox ® Fed Ratio 90% C.I. AUC_(0-t) 676.00 692.62 0.97600.8434-1.1294 AUC_(0-∞) 735.77 762.64 0.9648 0.8337-1.1164 C_(max) 69.9250.11 1.3954 1.1533-1.6882 Fed Multiple dose, low dose 10850705 (N = 24)Parameter 2 x SUBA ® 2 x Sporanox ® Ratio 90% C.I. AUC_(0-t) 12212 146490.8336 0.7535-0.9222 AUC_(0-∞) 17438 21695 0.8038 0.6832-0.9456 C_(max)402 496 0.8107 0.7334-08962 Fed Multiple dose, high dose 10850706 (N =24) Parameter 4 x SUBA ® 4 x Sporanox ® Ratio 90% C.I. AUC₀₋₇₂ 44400.5067186.24 0.6609 0.5974-0.7310 AUC_(0-∞)* — — — — C_(max) 1042.83 1540.240.6771 0.6186-0.7410 2 Study HGN007 - Fed State (n = 35) Parameter 1 xSUBA ® 1 x Sporanox ® Ratio 90% C.I. AUC_(0-t) 359 358 1.00 0.827, 1.22 AUC_(0-∞) 521 591 0.883 0.774, 1.05  C_(max) 33.6 36.2 0.927 0.763,1.12  Study HGN007 - Fasted State (n = 35) Parameter 1 x SUBA ® 1 xSporanox ® Ratio 90% C.I. AUC_(0-t) 448 733 0.611 0.557, 0.670 AUC_(0-∞)591 866 0.682 0.629, 0.740 C_(max) 63.4 63.8 0.993 0.859, 1.15  StudyHGN008 - Fed State, Replicate Design (n = 48) Parameter 1 x SUBA ® 1 xSporanox ® Ratio 90% C.I. AUC_(0-tlast) 479 602 0.797 0.704, 0.901AUC_(0-∞) 611 800 0.763 0.678, 0.859 C_(max) 41.3 52.6 0.785 0.695,0.888

Example 4

The results of this study show a dose-proportional bioavailabilityrelationship for the bioavailability of SUBA®-Itraconazole at doses of50 mg, 60 mg and 70 mg for both AUC and Cmax. The bioavailability ofItraconazole from a single 100 mg dose of SPORANOX® was comparable tothe bioavailability of Itraconazole from the 50 mg dose ofSUBA®-Itraconazole.

Efficacy Study Example 14—a Randomized, Double Blind, Multiple-Site,Placebo-Controlled Study, Comparing the Efficacy and Safety ofSUBA™-Itraconazole Capsules Compared to SPORANOX® (Itraconazole)Capsules in the Treatment of Onychomycosis of the Toenail

Study Rationale

This study compared the relative efficacy and safety ofSUBA™-Itraconazole 50 mg Capsules to an already marketed oralformulation of itraconazole, SPORANOX® (itraconazole) 100 mg capsules,in the treatment of onychomycosis of the toenail. Both the test and thereference formulations were also compared to a placebo formulation totest for superiority.

Study Design

This study was a randomized, double-blind, multiple-site,placebo-controlled study comparing SUBA™-Itraconazole 50 mg capsules tothe currently marketed reference product SPORANOX® (itraconazole) 100 mgcapsules.

Patients with a confirmed diagnosis of moderate to severe onychomycosisof the toenail were randomized to one of three treatment groups asfollows:

Test Group: SUBA™-Itraconazole 2×50 mg capsules (100 mg dose) once a dayapproximately 30 minutes prior to breakfast for 12 weeks;

Reference Group: SPORANOX® (itraconazole) 2×100 mg capsules (200 mgdose) taken once a day with breakfast for 12 weeks; or

Placebo Group: 2×placebo capsules taken once a day approximately 30minutes prior to breakfast for 12 weeks.

One hundred seventy-five (175) patients were enrolled in the study.Seventy-six (76) patients were enrolled in the Test group, 75 in theReference group and 24 in the Placebo group. The three primary efficacyendpoints in the study were the proportion of patients considered aTherapeutic Cure, Clinical Cure and Mycological Cure, 24 weeks afterstarting treatment. Safety was evaluated by comparing adverse events,monitoring vital signs, EKG parameters, audiology and changes inclinical laboratory results obtained throughout the study.

Eligible patients were randomly assigned in a 3:3:1 ratio to the Testformulation 100 mg (2×50 mg capsules) once a day, Reference formulation200 mg (2×100 mg capsules) once a day, or Placebo (2×capsules) once aday for 12 weeks of treatment.

Non-inferiority was determined by evaluating the difference between theproportion of patients in the Test and Reference groups who wereconsidered:

-   -   1) a Therapeutic Cure at the End of Study Visit (Week 24);    -   2) a Clinical Cure at the End of Study Visit (Week 24); or    -   3) a Mycological Cure at the End of Study Visit (Week 24).

The intent to treat population (ITT) was used for the primary analysisof non-inferiority.

The superiority of the test and reference formulations against thePlacebo was tested using the same 3 dichotomous endpoints. The ITT wasused for all analysis of superiority.

There were 4 secondary endpoints:

-   -   1) The proportion of patients in each treatment group who were        considered a Therapeutic Cure at the End of Treatment (Week 12);    -   2) The proportion of patients in each treatment group who were        considered a Clinical Cure at the End of Treatment (Week 12);    -   3) The proportion of patients in each treatment group who were        considered a Mycological Cure at the End of Treatment (Week 12);    -   4) The proportion of patients in each treatment group who showed        a relapse during the study. Relapse was defined as being a        Mycological Cure at Week 12 but being re-infected at Week 24

All secondary endpoints were tested for superiority against Placebo. TheITT was used for all secondary analysis of non-inferiority andsuperiority.

Statistical Methods

All statistical analysis was conducted using SAS®, Version 9.1.3.

Baseline comparability of all treatment groups was compared usingappropriate statistical tests (e.g., one way analysis of variance,Cochran-Mantel-Haenszel Test). The groups were compared for basicdemographics (age, gender, ethnicity, race), number of previousonychomycosis infections of the toenails, estimated duration of currentinfection, number of toes infected, % of toe infected, infectingorganism (presence or absence of T. rubrum and presence or absence of T.mentagrophytes), presence or absence of concurrent tinea pedis infectionand total NIRS score.

The primary measure of non-inferiority of the Test group to theReference group was evaluated using those patients eligible forinclusion in the ITT. The three primary endpoints of the study were; theproportion of patients who were considered a Therapeutic Cure, ClinicalCure and Mycological Cure at the End of Study Visit (Week 24).

To demonstrate non-inferiority an upper bound 95% confidence intervalapproach comparing the difference between the cure rate in the Test andthe Reference groups was used. If the lower bound 95% confidenceinterval of the difference between the proportion of patients in theTest group compared to the Reference group considered a TherapeuticCure, Clinical Cure and Mycological Cure as appropriate, at Week 24 wasgreater than −20 then non-inferiority was considered to have beendemonstrated. Secondary measures of non-inferiority also used the ITT.

For each of the four dichotomous secondary endpoints, the samestatistical analysis as used for the primary endpoint was used.Specifically if the lower bound 95% confidence interval of thedifference between the proportion of patients in the Test group comparedto the Reference group considered a cure at the visit being analyzed wasgreater than −20 then non-inferiority was considered to have beendemonstrated. All primary and secondary endpoints were tested forsuperiority against Placebo. The ITT was used for all superioritytesting.

For the three primary endpoints and all four dichotomous secondaryendpoints, if the difference between the proportion of patientsconsidered a cure in the Test or Reference group was statisticallygreater (p<0.05) than the proportion of patients considered a cure inthe Placebo group, then superiority of that treatment over placebo wasconsidered to have been demonstrated. A one-sided continuity correctedZ-test was used for superiority testing.

Safety analysis included all patients who were randomized and used studymedication on at least one occasion. For the analysis of clinicallaboratory testing descriptive analyses (mean, standard deviation,median, maximum and minimum) of each laboratory parameter werecalculated at each time point by treatment group. Shift analysis usingthe categories; below, above and within the laboratory normal range wasperformed to identify any specific laboratory parameter that showed atrend to show potentially clinically significant changes.

Comparative Efficacy Analysis

The primary measure of non-inferiority of the Test group to theReference group was evaluated using those patients eligible forinclusion in the ITT. The three primary endpoints of the study were theproportion of patients in each treatment group who were considered aTherapeutic Cure, Clinical Cure and Mycological Cure at the End of StudyVisit (week 24). A patient was considered a Therapeutic Cure if theywere both a Clinical Cure (NIRS of 0) and a Mycological Cure (negativeKOH and mycological culture). Any patient who was discontinued from thestudy prior to Visit 7 because of lack of efficacy was automaticallyconsidered a Clinical Failure and thus a Therapeutic Failure. If thelower bound 95% confidence interval of the difference between theproportion of patients in the Test group compared to the Reference groupconsidered a Therapeutic Cure, Clinical Cure or Mycological Cure asappropriate at Visit 7 was greater than −20, then non-inferiority wasconsidered to have been demonstrated.

All primary and secondary endpoints were tested for superiority againstPlacebo. The ITT was used for all secondary analysis of non-inferiorityand superiority. Any patient who was discontinued from the study priorto Visit 7 because of lack of efficacy was considered a ClinicalFailure. If a sample for KOH and/or mycological culture was obtained,the result was carried forward for later visits.

For each of the four secondary endpoints, the same statistical analysisas used for the primary endpoint was performed. Specifically, if thelower bound 95% confidence interval of the difference between theproportion of patients in the test group compared to the reference groupconsidered a cure at the visit being analyzed was greater than −20 thennon-inferiority was considered to have been demonstrated.

Superiority to Placebo Analysis

The ITT was used for all superiority testing. For the three primaryendpoints and all four secondary endpoints, if the difference betweenthe proportion of patients considered a cure was statistically greater(p<0.05) than the proportion of patients considered a cure in thePlacebo group, then superiority was considered to have beendemonstrated. A one-sided continuity corrected Z-test was used forsuperiority testing.

A summary of the results from this study is shown in Tables 73-78 whichshow that SUBA™-Itraconazole is superior to placebo for mycologicalcure.

TABLE 73 Summary of Results: Non-Inferiority (Primary Analysis) PrimaryAnalysis - Non Inferiority Intent-to-Treat Population (ITT) TherapeuticCure at Visit 7 (Week 24) N Therapeutic Cure Difference Lower 95% CITest 76  8 (10.53%) 6.47 −1.77 Ref 74 3 (4.05%) Clinical Cure at Visit 7(Week 24) N Clinical Cure Difference Lower 95% CI Test 76 12 (15.79%)10.38 0.92 Ref 74 4 (5.41%) Mycological Cure at Visit 7 (Week 24) NMycological Cure Difference Lower 95% CI Test 76 25 (32.89%) 3.17 −10.62Ref 74 22 (29.73%)

TABLE 74 Summary of Results: Non-Inferiority (Secondary Analysis)Secondary Analysis - Non Inferiority (ITT) Therapeutic Cure at Visit 6(Week 12) N Therapeutic Cure Test 76 0 (0.00%) Ref 74 0 (0.00%) ClinicalCure at Visit 6 (Week 12) N Clinical Cure Difference Lower 95% CI Test76 1 (1.32%) 1.32 −2.17 Ref 74 0 (0.00%) Mycological Cure at Visit 6(Week 12) N Mycological Cure Difference Lower 95% CI Test 76 16 (21.05%)−0.57 −12.91 Ref 74 16 (21.62%) Mycological Relapse Between TreatmentGroups (Visit 6 to Visit 7) N Relapse Difference Lower 95% CI Test 16  3(18.75%) −6.25 −36.47 Ref 16  4 (25.00%)

TABLE 75 Summary of Results: Superiority (Primary Analysis) PrimaryAnalysis - Superiority (ITT) Therapeutic Cure at Visit 7 (Week 24) NTherapeutic Cure Comparison One sided p-value Test 76  8 (10.53%) Testv. Placebo p = 0.0135* Ref 74 3 (4.05%) Ref v. Placebo p = 0.2861Placebo 24 0 (0.00%) Clinical Cure at Visit 7 (Week 24) N Clinical CureComparison One sided p-value Test 76 12 (15.79%) Test v. Placebo p =0.0009* Ref 74 4 (5.41%) Ref v. Placebo p = 0.1570 Placebo 24 0 (0.00%)Mycological Cure at Visit 7 (Week 24) N Mycological Cure Comparison Onesided p-value Test 76 25 (32.89%) Test v. Placebo p = 0.0001* Ref 74 22(29.73%) Ref v. Placebo p = 0.0003* Placebo 24 1 (4.17%) *Statisticallysignificant if p < 0.05

TABLE 76 Summary of Results: Superiority (Secondary Analysis) SecondaryAnalysis - Superiority (ITT) Therapeutic Cure at Visit 6 (Week 12) NTherapeutic Cure Test. 76 0 (0.00%) Ref 74 0 (0.00%) Placebo 24 0(0.00%) Clinical Cure at Visit 6 (Week 12) N Clinical Cure ComparisonOne sided p-value Test 76 1 (1.32%) Test v. Placebo p = 0.1377 Ref 74 0(0.00%) Placebo 24 0 (0.00%) Mycological Cure at Visit 6 (Week 12) NMycological Cure Comparison One sided p-value Test 76 16 (21.05%) Testv. Placebo p = 0.2396 Ref 74 16 (21.62%) Ref v. Placebo p = 0.2210Placebo 24  3 (12.50%) Mycological Relapse Between Treatment Groups(Visit 6 to Visit 7) N Relapse Comparison One sided p-value Test 16  3(18.75%) Test v. Placebo p = 0.0096 Ref 16  4 (25.00%) Ref v. Placebo p= 0.0179* Placebo 3  2 (66.67%) *Statistically significant if p < 0.05

TABLE 77 Interim Visit Efficacy Analysis - Non-Inferiority Interim VisitEfficacy Analysis - Non Inferiority (ITT) Therapeutic Cure at Visit 4(Week 6) N Therapeutic Cure Test 76 0 (0.00%) Ref 74 0 (0.00%) ClinicalCure at Visit 4 (Week 6) N Clinical Cure Test 76 0 (0.00%) Ref 74 0(0.00%) Mycological Cure at Visit 4 (Week 6) N Mycological CureDifference Lower 95% CI Test 76 11 (14.47%) 7.72 −1.81 Ref 74 5 (6.76%)

TABLE 78 Interim Visit Analysis - Superiority Interim Visit SuperiorityAnalysis (ITT) Therapeutic Cure at Visit 4 (Week 6) N Therapeutic CureTest 76 0 (0.00%) Ref 74 0 (0.00%) Placebo 24 0 (0.00%) Clinical Cure atVisit 4 (Week 6) N Clinical Cure Test 76 0 (0.00%) Ref 74 0 (0.00%)Placebo 24 0 (0.00%) Mycological Cure at Visit 4 (Week 6) N MycologicalCure Comparison One sided p-value Test 76 11 (14.47%) Test v. Placebo p= 0.0018* Ref 74 5 (6.76%) Ref v. Placebo p = 0.0853 Placebo 24 0(0.00%) *Statistically significant if p < 0.05

As shown in FIG. 58, SUBA™-Itraconazole was significantly superior toplacebo for both efficacy endpoints, whereas SPORANOX® (itraconazole)was not significantly different to placebo.

The more reliable extent of exposure following administration ofSUBA′-Itraconazole compared with SPORANOX® (itraconazole) may result infaster accumulation of itraconazole in the nail bed, clearing theinfection more quickly and allowing a faster clinical cure.

Moreover, the results of this study are clinically significant. As shownin FIG. 59, which illustrates the cure rates for this study with theLION Study (Evans et al. 1999), the cure rates for LOZANOC at week 24are comparable to terbinafine pulse therapy and are higher than would beexpected for conventional itraconazole. For all comparisons, p<0.0001except for clinical cure T₁₂ v I₃ where p<0.0015; T₁₂ V I₄ p=0.0022; andfor complete cure T₁₂ V I₃ p=0.0007 and T₁₂ v I₄ p=0.0044.

SUB^(ATM)-Itraconazole Capsule dosed at 100 mg once a day has been shownto be non-inferior to SPORANOX® (itraconazole) capsule dosed at 200 mgonce a day in the treatment of onychomycosis of the toenail, as measuredusing the primary endpoints of Therapeutic Cure, Clinical Cure andMycological Cure at Week 24.

The Test formulation was shown to be superior to Placebo for each of thethree endpoints at Week 24. The Reference product was shown to besuperior to Placebo for Mycological Cure, but not Clinical Cure orTherapeutic Cure at Week 24.

For the secondary endpoints of Clinical Cure and Mycological Cure atWeek 12, the Test formulation was shown to be non-inferior to theReference product. Because of the small sample size neither treatmentwas superior to Placebo for these secondary endpoints. There were noTherapeutic Cure's in any group at Week 12.

Mycological relapse rate was lower (18.75%) in the Test group than theReference group (25.00%) but the small sample size (N=16 in each group)did not allow for statistical non-inferiority. Both Test and Referenceformulations were superior to Placebo (66.67%) in relapse rate.

SUBA™-Itraconazole Capsule dosed at 100 mg once a day was demonstratedto have a similar safety profile to SPORANOX® (itraconazole) capsuledosed at 200 mg once a day.

Analysis of Adverse Events

All 175 patients enrolled in the study were included in the adverseevent analysis. Ninety (90) patients reported a total of 219 adverseevents during the study. Fisher's exact test analysis was performed foradverse events reported at least once in two or more treatment groups.There were no significant differences in the frequency of adverse eventsbetween the treatment groups. There were no significant differencesbetween the Test and the Reference groups with respect to type,frequency or severity or adverse events reported or observed during thestudy. The safety profile of SUBA′-Itraconazole Capsule dosed at 100 mgonce a day is consistent with the known safety profile to SPORANOX®(itraconazole) capsule dosed at 200 mg once a day. No significantly newor unexpected adverse events attributable to itraconazole were observedin this study.

Example 15—Comparison of AUC/MIC Ratios and Relationship to ClinicalEfficacy

Itraconazole has been used to treat a wide variety of fungal infectionssince its first introduction into clinical practice. For instance, withboth the 100 mg capsule (SPORANOX®) form of itraconazole and the oralsolution, there are data in oropharyngeal candidosis to establish arelationship between minimum inhibitory concentration (MIC) value, serumlevel, and clinical response (Cross, Bagg et al. 2000). Inaspergillosis, it has been more difficult to establish a relationshipbetween MIC values and clinical responses given that many infectionsalso occur in teh context of severe immunosuppression leading to greaterunpredictability. However, in a muring model of aspergillosis, a similarpositive predictive value of MIC determination and clinical response wasseen (Denning, Radford et al. 1997). Notably, some strains ofAspergillus fumigatus show MIC values at the upper range. However,resistance to trazole antifungals occurs in fewer than 2% of strains andthere is evidence that there is cross resistance between itraconazole,posaconazole, and voriconazole (Pfaller, Boyken et al. 2011).

There is limited evidence for a relationship between MIC level andclinical breakpoints for other systemic infections, such ashistoplasmosis, However the relationship between the low MICs forHistoplasma capsulatum and its clinical efficacy are sufficientlyconsistent to continue to recommend this drug as primary treatment ofhistoplasmosis.

Given that: i) oral itraconazole has been successfully used for decadesto treat a wide range of superficial and systemic fungal infections; andii) LOZANOC 50 mg hard capsules and SPORANOX® 100 mg Capsules containthe same drug substance, the goal of a comparison of AUC/MIC ratios forthe two formulations is not to predict the clinical efficacy ofitraconazole. Rather, it is to assess: 1) the probability that a LOZANOC50 mg hard capsule patient will achieve a lower exposure than isnecessary for therapeutic effect compared to tghe correspondingprobability with SPORANOX® 100 mg Capsules; and 2) the probability thata LOZANOC 50 mg hard capsule patient will achieve a much greaterexposure than is necessary compared to the corresponding probabilitywith SPORANOX® 100 mg Capsules.

Tables 79A and 79B list the typical infecting organisms for specificsuperficial and systemic mycoses and their corresponding MIC ranges.

TABLE 79A INDICATIONS INFECTING ORGANISM MIC RANGE Superficial mycosesDermatomycoses tinea Trichophyton sp. (rubrum, tonsurans interdigitale,0.01-8 corporis mentagrophytes, concentricim, violaceum et al.) MIC₉₀ =0.25-0.5 Microsporum sp. (canis, gypseum, et al.) 0.01-4 MIC₉₀ =0.25-0.5 Epidermophyton floccosum 0.01-8 MIC₉₀ = 0.125 tineaTrichophyton sp. (rubrum, tonsurans interdigitale, 0.01-8 crurismentagrophytes, et al.) MIC₉₀ = 0.25-0.5 Microsporum sp. (canis, et al.)0.01-4 MIC₉₀ = 0.25-0.5 Epidermophyton floccosum 0.01-8 MIC₉₀ = 0.125tinea Trichophyton sp. (rubrum, tonsurans interdigitale, 0.01-8 pedismentagrophytes, et al.) MIC₉₀ = 0.25-0.5 Microsporum sp. (canis,gypseum, et al.) 0.01-4 MIC₉₀ = 0.25-0.5 Epidermophyton floccosum 0.01-8MIC₉₀ = 0.125 tinea Trichophyton sp. (rubrum, interdigitale, 0.01-8manuum mentagrophytes.) MIC₉₀ = 0.25-0.5 Epidermophyton floccosum 0.01-8MIC₉₀ = 0.125 tinea Trichophyton sp. (rubrum, tonsurans interdigitale,0.01-8 unguium mentagrophytes, et al.) MIC₉₀ = 0.25-0.5 Microsporum sp.(canis, et al.) 0.01-4 MIC₉₀ = 0.25-0.5 Epidermophyton floccosum 0.01-8MIC₉₀ = 0.125 tinea Trichophyton sp. (tonsurans violaceum, soudanese,0.01-8 capitis schoenleinii, mentagrophytes, verrucossum, et al.) MIC₉₀= 0.25-0.5 Microsporum sp. (audounti, canis, gypseum, 0.01-4 ferrugineumet al. MIC₉₀ = 0.25-0.5 Pityriasis versicolor Malassezia sp. (florfur,globosa, obtuse, 0.3-16 sympodialis etc). MIC₉₀ = 0.125

TABLE 79B INDICATIONS INFECTING ORGANISM MIC RANGE Systemic mycosesCandidiasis C. albicans 0.008-8 MIC₉₀ = 0.125 C. parapsilosis 0.016-2MIC₉₀ = 0.25 C. glabrata 0.008-16 MIC₉₀ = 16 C. kruset 0.008-8 MIC₉₀ =0.5 C. tropicalis 0.03-8 MIC₉₀ = 0.5 Aspergillosis A. fumigatus complex0.03-16 MIC₉₀ = 0.5 A. flavus complex 0.03-8 MIC₉₀ = 0.5 A. terreuscomplex 0.03-1 MIC₉₀ = 0.25 A. nidulans complex 0.03-8 MIC₉₀ = 0.25 A.niger complex 0.03-8 MIC₉₀ = 0.5 Histoplasmosis H. capsulatum 0.03-8MIC₉₀ = 0.06

When reviewing Table 79, the following should be noted:

All dermatophytes have the ability to cause infection of keratinaceoussubstrates like skin, hair, and nails. Species listed in this table arethe most common for the clinical entity described (Rippon 1988; Elewski1998).

In general, dermatophytes are generally considered to be fullysusceptible to itraconazole, resistant strains are very uncommon.However the MIC data presented is a composite of reports that may usedifferent methodology; standardised CLSI methodology for testingantifungal susceptibility to dermatophytes only became available in 2008(CLSI document M38-A2) (Fernandez-Tones, Carrillo et al. 2001;Sabatelli, Patel et al. 2006; Santos and Hamdan 2006).

With regards to pityriasis veriscolor, seven species of Malassezia havenow been recognised as causative agents. Antifungal susceptibilitytesting is difficult because they do not grow readily on the usualmedia. However, all are considered susceptible to itraconazole (Gueho,Midgley et al. 1996; Nakamura, Kano et al. 2000; Velegraki, Alexopouloset al. 2004; Miranda, de Araujo et al. 2007).

Several species of Candida may be aetiological agents, most commonly C.albicans (˜48%), followed by C. parapsilosis (˜19%), C. glabrata (˜18%),C. krusei (˜5%) and C. tropicalis (˜5%). However, a number of otherspecies may also be isolated (˜5% eg C. dubliensis, C. guilliermondii,C. lustianiae, C. kefry etc). All are ubiquitous and occur naturally onhumans. CLSI and EUCAST antifungal susceptibility methodology isavailable. Resistance to itraconazole (MIC>1 μg/ml) has been detected inmost species; however, it occurs predominantly in isolates of C.glabrata (Espinel-Ingroff 2001; Pfaller, Messer et al. 2002; Hajjeh,Sofair et al. 2004; Richter, Galask et al. 2005; Chen, Slavin et al.2006; Cuenca-Estrella, Gomez-Lopez et al. 2006; Pfaller and Diekema2007; Ellis and Handke 2010).

Overall, itraconazole resistance in Aspergillus remains low. Theemergence of invasive infection due to triazole-resistant, includingcross-resistant, A. fumigatus isolates is of increasing concern inEurope, where 3-6% of isolates have been reported resistant at differentcentres. However, to date, a similar emergence of triazole- and/orcross-resistant A. fumigatus has not been observed in the Australiansetting. A recent surveillance study of all A. fumigatus isolates at TheAlfred Hospital, Melbourne, identified no triazole-resistant A.fumigatus isolates over a one year period (May 2009-April 2010)(Espinel-Ingroff 2001; Espinel-Ingroff, Boyle et al. 2001; Pfaller,Messer et al. 2002; Cuenca-Estrella, Gomez-Lopez et al. 2006; Sabatelli,Patel et al. 2006; Verweij, Mellado et al. 2007; Kidd, Handke et al.2011) (S. Kidd, unpublished data).

Itraconazole is an important antifungal for the management ofhistoplasmosis (Espinel-Ingroff 2001; Gonzalez, Fothergill et al. 2005;Sabatelli, Patel et al. 2006; Wheat, Freifeld et al. 2007)

If one assigns a clinical breakpoint and a target AUC/MIC ratio foroptimal therapeutic effect then the minimum AUC required can becalculated. As highlighted in Table 79, these breakpoints and AUC/MICratios vary according to the infecting organism so it is instructive toconsider multiple scenarios. For illustrative purposes, Table 80, liststhree scenarios selected based on the following rationale:

A MIC90 of <1 mcg/ml is appropriate for treating the majority ofsusceptible superficial and systemic infections within the proposedindications for this application

A MIC90 of >4 mcg/ml would normally be considered resistant but in somecases itraconazole is used to treat specific mycoses considered to bedue to an organism resistant at this level if clinically indicated

A MIC90 of 16 mcg/ml is the maximum point on the standard 0.0008-16mcg/ml testing range employed in mycology laboratories.

A target AUC/MIC ratio of greater than 25 has been designated in Table80, as it has been determined to be the ratio at which optimal efficacyrates are achieved for the triazole class (Andes 2003).

TABLE 80 Calculations of minimum AUC required for optimal therapeuticeffect Clinical Target Minimum AUC Scenario breakpoint AUC/MIC required¹number (mcg/ml) ratio (ng · hr/ml) 1 1 25 25 2 4 25 100 3 16 25 400¹Obtained by multiplying column 2 × column 3

In FIG. 60 the individual subject AUC_(inf) results were ranked in orderof lowest to highest for both test and reference, with the minimum AUCthresholds arrived at in Table 80 superimposed. This illustrates actualAUCs required for optimal therapeutic effect and compares the relativeperformance of Lozanoc 50 mg hard capsules and Sporanox® 100 mg Capsulesin Example 10 (see pharmacokinetics section).

FIG. 61 and FIG. 62 apply the same principles for each occurrence in thestudy described in Example 12.

Review of FIG. 61 and FIG. 62 highlights that regardless of theformulation, all subjects in the study described in Examples 10 and 12achieved an exposure sufficient to achieve above the desired AUC/MICratio for Scenarios 1 and 2. As one might expect for oral itraconazole,the majority but not all subjects achieved an exposure sufficient toachieve above the desired AUC/MIC ratio for Scenario 3, with no apparentdifference between the formulations.

The most important pharmacokinetic-pharmacodynamic (PK-PD) parameter foritraconazole is the AUC/MIC ratio which should be greater than 25 foroptimal efficacy. The above data demonstrate that 50 mg of the testproduct, taken in the fed state, achieves this comfortably for the abovelisted organisms and with more certainty compared to the highly variableSporanox for MIC90>4 mcg/ml and also for the majority when MIC>16mcg/ml.

A key question is whether Lozanoc 50 mg hard capsules should be taken inthe fed or the fasted state, or whether it can be taken regardless offood. The study described in Example 10 indicated that Lozanoc 50 mgHard Capsules taken in the fed state performed better than in the fastedstate. However, three observations suggest that Lozanoc 50 mg hardcapsules can be taken regardless of food:

1. In the study described in Example 10, the variance in AUC(0-inf) forLozanoc 50 mg hard capsules is significantly lower than Sporanox® 100 mgCapsules when the fed and fasted data are pooled, which in part is dueto the variance being significantly less when Lozanoc 50 mg hardcapsules are taken in the fasted state versus Sporanox® 100 mg Capsulesin the fed state.

2. When one then compares the individual AUC/MIC ratios for subjects inthe study described in Example 10: (i) taking Lozanoc 50 mg hardcapsules in the fasted state versus Sporanox® 100 mg Capsules in the fedstate (FIG. 63) and (ii) Lozanoc 50 mg Hard Capsules in the fasted stateversus the fed state (FIG. 64), it is apparent that the performance ofLozanoc 50 mg hard capsules is comparable regardless of food.

3. In the onychomycosis efficacy study described in Example 14, Lozanoc50 mg hard capsules was dosed in the fasted state (30 minutes prior tobreakfast) and at week 24 demonstrated superior efficacy rates toplacebo.

The most important PK-PD parameter for itraconazole is the AUC/MIC ratiowhich should be greater than 25 for optimal efficacy. The above datademonstrate that 50 mg of the test product, taken in fasted state,achieves this comfortably for the above listed organisms and with morecertainty compared to the highly variable Sporanox for MIC90>4 mcg/mland also for the majority when MIC>16 mcg/ml.

Sporanox is an established antifungal agent for the treatment of a widevariety of superficial and systemic fungal infections. It is widely useddespite the known problems of high inter- and intra-individualvariation. To get the “right” dose, frequent drug level monitoring maybe required.

Lozanoc 50 mg hard capsules has demonstrated advantages over thereference, such as lower inter and intra-individual variability, lesspronounced food effect and therefore more predictability of dosing. Inaddition, the PK-PD parameter demonstrates that Lozanoc 50 mg hardcapsules achieves the AUC/MIC ratio which should be greater than 25 foroptimal efficacy in both the fed and fasted state for a number oforganisms.

The clinical study in onychomycosis demonstrated superiority of Lozanoc50 mg hard capsules compared to placebo. However Lozanoc 50 mg hardcapsules can be considered a therapeutic alternative to Sporanox in thetreatment of certain superficial and systemic mycoses.

Example 16—Study of 65 mg Dose LOZANOC

Study Rationale

This study will evaluate the relative bioavailability of a new strengthof SUBA®-itraconazole capsules with 65 mg itraconazole (“test capsules”)compared to SPORANOX® 100 mg itraconazole capsules when administered tohealthy adult subjects as single oral doses under fasted and fedconditions.

Study Design

The study will be a randomized, single-dose, four treatment, fourperiod, crossover, open-label, analytically blinded study for comparingsingle oral doses of the Test SUBA®-itraconazole 65 mg capsules tosingle oral doses of the Reference SPORANOX® (itraconazole) 100 mgcapsules under fasted and fed conditions. In each of four study periods,a single oral dose of itraconazole will be administered to all subjectseither as (1×65 mg) SUBA®-itraconazole capsule or (1×100 mg) SPORANOX®(itraconazole) capsule.

In two of the study periods, subjects will be dosed with either Test orReference Products following an overnight fast of at least 10 hours.After dosing, all subjects will continue to fast for an additional 4hours post-dose. In the other two study periods, subjects will be dosedwith either Test or Reference Product following the FDA standardizedhigh fat, high calorie breakfast, preceded by an overnight fast of atleast 10 hours. Subjects following the standardized high fat breakfastregimen will be administered their study treatment (dose) 30 minutesafter starting their meal. Each study treatment/dose will beadministered with 240 mL of ambient temperature water and any otherfluids (other than the milk given with the ‘fed’ breakfast) will berestricted from one hour pre-dosing until one hour post-dose. Water willbe encouraged ad lib at other times.

Study Population

Fifty two (52) healthy, non-tobacco using, adult male and non-pregnantfemale subjects, who satisfy all entry criteria, will be enrolled in thestudy. Enrolled subjects will be aged from 18 to 65 years and with abody mass index (BMI) between 18.0 and 30.0 kg/m2, inclusive.

Study Treatments

Test (A): 1×SUBA®-itraconazole 65 mg capsule following an overnight fastof at least 10 hours.

Test (B): 1×SUBA®-itraconazole 65 mg capsule following a standardizedhigh fat breakfast, preceded by an overnight fast of at least 10 hours.

Reference (C): 1×SPORANOX® (itraconazole) 100 mg capsule following anovernight fast of at least 10 hours.

Reference (D): 1×SPORANOX® (itraconazole) 100 mg capsule following astandardized high fat breakfast, preceded by an overnight fast of atleast 10 hours.

The subjects will receive the Test Product (SUBA®-itraconazole 65 mgcapsule) in two periods (once fasted and once fed) and the ReferenceProduct (SPORANOX® itraconazole 100 mg capsule) in the other two periods(once fasted and once fed); with the order of administration inaccordance with the 4 sequence dosing randomization schedule.

Single dosages will be administered in each study treatment period, andthere will be at least a 14-day washout interval between the fourdose/treatment administrations.

In each study period, blood samples for pharmacokinetic analysis will becollected pre-dose (0.0 h) and at 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0,4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 16, 24.0,36.0, 48.0, 72.0*, 96.0* and 120* hours post-dose administration. The *indicates return samples

Pharmacokinetic Analysis

The following pharmacokinetic information will be calculated foritraconazole and hydroxyitraconazole, the latter for informationalpurposes:

Plasma concentrations and time points

Subject, period, sequence, treatment

AUC0-t, AUC0-inf, Cmax, Tmax, Kel, and T½

Inter-subject, intra-subject, and/or total variability, if available.

The statistical information provided for AUC0-t, AUC0-inf, Cmax will bethe geometric mean, the arithmetic mean, the ratio of means andconfidence intervals (CI), with log transformation provided for measuresused to demonstrate bioequivalence. Equivalence will have beendemonstrated if the 90% CI for the Test/Reference ratio for AUC0-t,AUC0-inf, and Cmax for itraconazole falls within the range80.00-125.00%. Equivalence will be tested under fasting conditions (TestA v Reference C), and fed conditions (Test B v Reference D). Thereference range will be expanded for AUC0-t, AUC0-inf, and Cmax asappropriate for a highly variable drug based on the within-subjectvariability as assessed by ANOVA. Intersubject variability in AUC willbe assessed to test the hypothesis that SUBA®-itraconazole 65 mg capsuleproduce less variable itraconazole exposure than SPORANOX® itraconazole100 mg capsules.

The median, range and inter-quartile range (IQR) of AUC0-t and AUC0-infwill be compared between Test A and Reference C (fasted) and betweenTest B and Reference D (fed). Variability in AUC0-t and AUC0-inf will becompared graphically using Box-plots, and differences in variancebetween the Test and Reference formulations assessed via the Bartlett'stest.

Statistical Analysis

The pharmacokinetic and statistical analyses will be performed inaccordance with the relevant FDA Guidances for Industry.

Bioequivalence will be based on itraconazole pharmacokinetic parameters,although full pharmacokinetics and statistical analyses will beperformed on the hydroxyitraconazole data.

Subjects who complete at least two periods of the study will be includedin the final data set.

The Statistical Analysis System (SAS) will be used for allpharmacokinetic and statistical calculations. Linear andsemi-logarithmic graphs of the concentration-time profiles for eachsubject will be provided, using the actual times of sample collections.Graphical presentations of mean results will use the scheduled times ofsample collections. A complete listing of the deviations from the actualsampling times will be provided. Concentration values reported for eachcollected sample will be provided.

Data from subjects with missing concentration values (missed blooddraws, lost samples, samples unable to be quantified) may be used ifpharmacokinetic parameters can be estimated using remaining data points,otherwise data from these subjects will be excluded from final analysis.

For all treatments, the following pharmacokinetic information will becalculated for itraconazole and hydroxyitraconazole, the latter forinformational purposes:

Cmax will be the observed maximum plasma concentration.

Tmax will be the collection time at which Cmax is first observed.

AUC0-t, the area under the plasma concentration versus time curve fromtime 0 to the last measurable concentration, will be calculated by thelinear trapezoidal method;

AUC0-inf, the area under the plasma concentration versus time curve fromtime 0 to infinity will be calculated as the sum of AUC0-t plus theratio of the last measurable plasma concentration (Ct) to theelimination rate constant (Kel).

Kel, the apparent first-order terminal rate constant will be calculatedfrom a semi-log plot of the plasma concentration versus time curve. Theparameter will be calculated by linear least-squares regression analysisusing the maximum number of points in the terminal log-linear phase(e.g., three or more non-zero plasma concentrations).

T½, the apparent first-order terminal half-life will be calculated asln(2)/Kel.

No concentration estimates will be provided for missing sample values.Any sample with a missing value will be treated as if the sample had notbeen scheduled for collection.

Individual and mean results for all derived parameters and for theconcentrations at each scheduled collection time will be presented insummary tabulations. If a subject has a pre-dose (0 hour sample) plasmalevel for an analyte that is greater than 5% of their measured Cmaxvalue, the subject will be dropped from all BE study evaluations. Ifmeasurable plasma levels are equal to or less than 5% of their measuredCmax, the subject's data will be included in all pharmacokineticmeasurements without adjustment.

Data from subjects who experience emesis during the first 10 hourspost-dosing (based on approximately 2×the Tmax of approximately 5 hours)will be dropped from that period of the study and their samples fromthat period not analyzed.

To determine relative bioavailability and food effects, Analyses ofVariance will be performed using the MIXED procedure of SAS withhypothesis testing for treatment effects at α=0.05. The itraconazoletreatments will be tested separately under fed and fasted conditions andwill be repeated for hydroxyitraconazole for informational purposes. Asthe variance for all pharmacokinetic parameters increases as the meanincreases, the parameters will be log-transformed (base e) prior toanalysis. Using bioavailability as an example, the residual variancefrom the mixed model will be used to calculate 90% CI for the differencebetween the test and reference investigational products. These valueswill be back-transformed to give geometric LS means, a point estimateand 90% CI for the ratio of the test investigational product relative tothe reference investigational product. This procedure is equivalent toSchuirmann's two one-sided tests at the 0.05 level of significance.Equivalence will have been demonstrated if the 90% confidence intervalfor the Test/Reference ratio for AUC0-t, AUC0-inf, and Cmax foritraconazole falls within the standard reference range 80.00-125.00%.Residual plots will be produced to assess the adequacy of the model.

Bioequivalence will be tested under fasting conditions (Test A vReference C), and fed conditions (Test B v Reference D) 7-9. The effectof food on each formulation will be based on the log-transformed datafor itraconazole by comparing Test A v Test B and Reference C vReference D. If the 90% confidence interval for the Test/Reference ratiofor AUC0-t, AUC0-inf and Cmax for itraconazole all fall in the range80.00-125.00% in the fed state compared to the fasted state, then foodwill be considered not to have any effect on the bioavailability of thatformulation. The relative bioavailability of a single 65 mg capsule doseof the Test formulation under fasted conditions compared to a single 100mg capsule dose of the Reference formulation under fed conditions (A vD) will be presented for informational purposes. The reference range forthe 90% confidence interval will be expanded for AUC0-t, AUC0-inf, andCmax based on within-subject variability using the limits described inKaralis et al. for highly variable drugs.13

The parameter tmax will be analysed nonparametrically using the Wilcoxonsigned-rank test.

An additional data analysis will conducted to compare the inter-subjectvariability in itraconazole exposure. The distributions oflog-transformed and untransformed AUC0-t, AUC0-inf and Cmax will becompared graphically between Test and Reference in Fasted and Fedconditions using boxplots. The hypothesis that the two formulationsdiffer in the variability of exposure will be examined using Bartlett'stests (significance level p=0.05).

Predicted Results

It is predicted that the 65 mg SUBA® formulation will be bioequivalentto the 100 mg SPORANOX® formulation. It is also predicted that the 65 mgSUBA® formulation will give AUC values that are between those of the 60mg formulation and 70 mg formulation (Example 4). Thus, the principlepharmacokinetic parameters may be those shown in Table 5.

Specific Embodiments of the Invention

1. An oral pharmaceutical composition comprising about 50 mg ofitraconazole, wherein the composition exhibits an AUC_(0-t) which is 80%to 125% of about 440 h*ng/ml to about 740 h*ng/ml followingadministration of the composition to a subject under fed conditions.

2. The oral pharmaceutical composition of embodiment 1, wherein thecomposition exhibits a C_(max) which is 80% to 125% of about 60 ng/ml toabout 75 ng/ml following administration of the composition to a subjectunder fed conditions.

3. The oral pharmaceutical composition of embodiment 1 or 2, wherein thecomposition exhibits reduced food effect as compared to a referencecomposition of itraconazole.

4. The oral pharmaceutical composition of any one of embodiments 1 to 3,which under fed conditions is therapeutically similar to a referencecomposition under fed conditions.

5. The oral pharmaceutical composition of embodiment 4, which under fedconditions is bioequivalent to the reference composition under fedconditions.

6. The oral pharmaceutical composition of any one of embodiment 1 to 3,which under fasting conditions is therapeutically similar to a referencecomposition under fed conditions.

7. The oral pharmaceutical composition of embodiment 6, which underfasting conditions is bioequivalent to the reference composition underfed conditions.

8. The oral pharmaceutical composition of any one of embodiments 1 to 7,wherein the composition under fed conditions is substantially similar tothe same composition under fasting conditions.

9. The oral pharmaceutical composition of embodiment 8, which exhibits adifference of less than about 35% between a AUC₀₋₁ under fastingconditions and a AUC₀₋₁ under fed conditions.

10. The oral pharmaceutical composition of any one of embodiments 1 to9, which exhibits reduced intra-subject variability as compared to areference composition of itraconazole.

11. The oral pharmaceutical composition of embodiment 10, which exhibitsa reduced variability in the AUC_(0-t) as compared to the referencecomposition.

12. The oral pharmaceutical composition of any one of embodiments 1 to11, which exhibits reduced inter-subject variability as compared to areference composition of itraconazole.

13. The oral pharmaceutical composition of embodiment 12, which exhibitsa reduced variability in the AUC_(0-t) as compared to the referencecomposition.

14. The oral pharmaceutical composition of any one of embodiments 1 to11, which exhibits a ratio in the range from about 0.70 to about 1.43for AUC_(0-t) between the oral pharmaceutical composition and areference composition with the 90% confidence interval.

15. The oral pharmaceutical composition of any one of embodiments 1 to14, which, upon administration under fed conditions, exhibits a relativebioavailability (F_(rel)) of greater than about 150% relative to areference composition under fed conditions.

16. The oral pharmaceutical composition of any one of embodiments 1 to15, which exhibits a minimum inhibitory concentration (MIC) value ofless than about 16 mcg/ml.

17. The oral pharmaceutical composition of any one of embodiments 1 to16, which exhibits an AUC/MIC ratio of about 25 or greater.

18. An oral pharmaceutical composition comprising about 50 mg ofitraconazole, wherein the composition exhibits an AUC_(0-t) which is 80%to 125% of about 350 h*ng/ml to about 620 h*ng/ml followingadministration of the composition to a subject under fasting conditions.

19. The oral pharmaceutical composition of embodiment 18, wherein thecomposition exhibits a C_(max) which is 80% to 125% of about 30 ng/ml toabout 60 ng/ml following administration of the composition to a subjectunder fasting conditions.

20. The oral pharmaceutical composition of embodiment 18 or 19, whereinthe composition exhibits reduced food effect as compared to a referencecomposition of itraconazole.

21. The oral pharmaceutical composition of any one of embodiments 18 to20, which under fed conditions is therapeutically similar to a referencecomposition under fed conditions.

22. The oral pharmaceutical composition of embodiment 21, which underfed conditions is bioequivalent to the reference composition under fedconditions.

23. The oral pharmaceutical composition of any one of embodiments 18 to20, which under fasting conditions is therapeutically similar to areference composition under fed conditions.

24. The oral pharmaceutical composition of embodiment 23, which underfasting conditions is bioequivalent to the reference composition underfed conditions.

25. The oral pharmaceutical composition of any one of embodiments 18 to24, wherein the composition under fed conditions is substantiallysimilar to the same composition under fasting conditions as to foodeffect.

26. The oral pharmaceutical composition of embodiment 25, which exhibitsa difference of less than about 35% between a AUC_(0-t) under fastingconditions and a AUC_(0-t) under fed conditions.

27. The oral pharmaceutical composition of any one of embodiments 18 to26, which exhibits reduced intra-subject variability as compared to areference composition of itraconazole.

28. The oral pharmaceutical composition of embodiment 27, which exhibitsa reduced variability in the AUC_(0-t) as compared to the referencecomposition.

29. The oral pharmaceutical composition of any one of embodiments 18 to28, which exhibits reduced inter-subject variability as compared to areference composition of itraconazole.

30. The oral pharmaceutical composition of embodiment 29, which exhibitsa reduced variability in the AUC_(0-t) as compared to the referencecomposition.

31. The oral pharmaceutical composition of any one of embodiments 18 to30, which exhibits a ratio in the range from about 0.70 to about 1.43for AUC_(0-t) between the oral pharmaceutical composition and areference composition with the 90% confidence interval.

32. The oral pharmaceutical composition of any one of embodiments 18 to31, which exhibits a minimum inhibitory concentration (MIC) value ofless than about 16 mcg/ml.

33. The oral pharmaceutical composition of any one of embodiments 18 to32, which exhibits an AUC/MIC ratio of about 25 or greater.

34. The oral pharmaceutical composition of any one of embodiments 18 to33, which, upon administration under fed conditions, exhibits a relativebioavailability (F_(rel)) of greater than about 150% relative to areference composition under fed conditions.

35. The oral pharmaceutical composition of any one of embodiments 18 to34, which exhibits an AUC which is 80% to 125% of about 440 h*ng/ml toabout 740 h*ng/ml following administration of the composition to asubject under fed conditions.

36. The oral pharmaceutical composition of embodiment 35, wherein thecomposition exhibits a C_(max) which is 80% to 125% of about 60 ng/ml toabout 75 ng/ml following administration of the composition to a subjectunder fed conditions.

37. The oral pharmaceutical composition of any one of embodiments 18 to36, which is therapeutically equivalent to a reference composition.

38. An oral pharmaceutical composition comprising about 65 mg ofitraconazole, wherein the composition exhibits an AUC_(0-t) which is 80%to 125% of about 650 h*ng/ml to about 1200 h*ng/ml followingadministration of the composition to a subject under fed conditions.

39. The oral pharmaceutical composition of embodiment 38, wherein thecomposition exhibits a C_(max) which is 80% to 125% of about 65 ng/ml toabout 100 ng/ml following administration of the composition to a subjectunder fed conditions.

40. The oral pharmaceutical composition of embodiments 38 or 39, whereinthe composition exhibits reduced food effect as compared to a referencecomposition of itraconazole.

41. The oral pharmaceutical composition of any one of embodiments 38 to40, which under fed conditions is therapeutically similar to a referencecomposition under fed conditions.

42. The oral pharmaceutical composition of embodiment 41, which underfed conditions is bioequivalent to the reference composition under fedconditions.

43. The oral pharmaceutical composition of any one of embodiments 38 to40, which under fasting conditions is therapeutically similar to areference composition under fed conditions.

44. The oral pharmaceutical composition of embodiment 43, which underfasting conditions is bioequivalent to the reference composition underfed conditions.

45. The oral pharmaceutical composition of any one of embodiments 38 to44, wherein the composition under fed conditions is substantiallysimilar to the same composition under fasting conditions as to foodeffect.

46. The oral pharmaceutical composition of embodiment 45, which exhibitsa difference of less than about 35% between a AUC_(0-t) under fastingconditions and a AUC_(0-t) under fed conditions.

47. The oral pharmaceutical composition of any one of embodiments 38 to46, which exhibits reduced intra-subject variability as compared to areference composition of itraconazole.

48. The oral pharmaceutical composition of embodiment 47, which exhibitsa reduced variability in the AUC_(0-t) as compared to the referencecomposition.

49. The oral pharmaceutical composition of any one of embodiments 38 to48, which exhibits reduced inter-subject variability as compared to areference composition of itraconazole.

50. The oral pharmaceutical composition of embodiment 49, which exhibitsa reduced variability in the AUC_(0-t) as compared to the referencecomposition.

51. The oral pharmaceutical composition of any one of embodiments 38 to48, which exhibits a ratio in the range from about 0.70 to about 1.43for AUC_(0-t) between the oral pharmaceutical composition and areference composition with the 90% confidence interval.

52. The oral pharmaceutical composition of any one of embodiments 38 to51, which, upon administration under fed conditions, exhibits a relativebioavailability (F_(rel)) of greater than about 150% relative to areference composition under fed conditions.

53. The oral pharmaceutical composition of any one of embodiments 38 to52, which exhibits a minimum inhibitory concentration (MIC) value ofless than about 16 mcg/ml.

54. The oral pharmaceutical composition of embodiment 53, which exhibitsan AUC/MIC ratio of about 25 or greater.

55. An oral pharmaceutical composition comprising about 65 mg ofitraconazole, wherein the composition exhibits an AUC_(0-t) which is 80%to 125% of about 450 h*ng/ml to about 900 h*ng/ml followingadministration of the composition to a subject under fasting conditions.

56. The oral pharmaceutical composition of embodiment 55, wherein thecomposition exhibits a C_(max) which is 80% to 125% of about 36 ng/ml toabout 70 ng/ml following administration of the composition to a subjectunder fasting conditions.

57. The oral pharmaceutical composition of embodiment 55 or 56, whereinthe composition exhibits reduced food effect as compared to a referencecomposition of itraconazole.

58. The oral pharmaceutical composition of any one of embodiments 55 to57, which under fed conditions is therapeutically similar to a referencecomposition under fed conditions.

59. The oral pharmaceutical composition of embodiment 58, which underfed conditions is bioequivalent to the reference composition under fedconditions.

60. The oral pharmaceutical composition of any one of embodiments 55 to59, which under fasting conditions is therapeutically similar to areference composition under fed conditions.

61. The oral pharmaceutical composition of embodiment 60, which underfasting conditions is bioequivalent to the reference composition underfed conditions.

62. The oral pharmaceutical composition of any one of embodiments 55 to61, wherein the composition under fed conditions is substantiallysimilar to the same composition under fasting conditions.

63. The oral pharmaceutical composition of embodiment 62, which exhibitsa difference of less than about 35% between a AUC_(0-t) under fastingconditions and a AUC_(0-t) under fed conditions.

64. The oral pharmaceutical composition of any one of embodiments 55 to63, which exhibits reduced intra-subject variability as compared to areference composition of itraconazole.

65. The oral pharmaceutical composition of embodiment 64, which exhibitsa reduced variability in the AUC_(0-t) as compared to the referencecomposition.

66. The oral pharmaceutical composition of any one of embodiments 55 to65, which exhibits reduced inter-subject variability as compared to areference composition of itraconazole.

67. The oral pharmaceutical composition of embodiment 66, which exhibitsa reduced variability in the AUC_(0-t) as compared to the referencecomposition.

68. The oral pharmaceutical composition of any one of embodiments 55 to67, which exhibits a ratio in the range from about 0.70 to about 1.43for AUC_(0-t) between the oral pharmaceutical composition and areference composition with the 90% confidence interval.

69. The oral pharmaceutical composition of any one of embodiments 55 to68, which, upon administration under fed conditions, exhibits a relativebioavailability (F_(rel)) of greater than about 150% relative to areference composition under fed conditions.

70. The oral pharmaceutical composition of any one of embodiments 55 to69, which exhibits an AUC_(0-t) which is 80% to 125% of about 650h*ng/ml to about 1200 h*ng/ml following administration of thecomposition to a subject under fed conditions.

71. The oral pharmaceutical composition of embodiment 70, wherein thecomposition exhibits a C_(max) which is 80% to 125% of about 65 ng/ml toabout 100 ng/ml following administration of the composition to a subjectunder fed conditions.

72. The oral pharmaceutical composition of embodiment 71, which istherapeutically equivalent to a reference composition.

73. The oral pharmaceutical composition of any one of embodiments 55 to72, which exhibits a minimum inhibitory concentration (MIC) value ofless than about 16 mcg/ml.

The oral pharmaceutical composition of embodiment 73, which exhibits anAUC/MIC ratio of about 25 or greater.

75. An oral pharmaceutical composition comprising itraconazole, whereinthe composition exhibits an AUC_(0-t) which is 80% to 125% of about 8.8h*ng/ml to about 14.8 h*ng/ml per milligram of itraconazole followingadministration of the composition to a subject under fed conditions.

76. The oral pharmaceutical composition of embodiment 75, wherein thecomposition exhibits a C_(max) which is 80% to 125% of about 1.2 ng/mlto about 1.5 ng/ml per milligram of itraconazole followingadministration of the composition to a subject under fed conditions.

77. The oral pharmaceutical composition of embodiment 75 or 76, whereinthe composition exhibits reduced food effect as compared to a referencecomposition of itraconazole.

78. The oral pharmaceutical composition of any one of embodiments 75 to77, which under fasting conditions is therapeutically similar to areference composition under fed conditions.

79. The oral pharmaceutical composition of any one of embodiments 75 to78, wherein the composition under fed conditions is substantiallysimilar to the same composition under fasting conditions.

80. The oral pharmaceutical composition form of any one of embodiments75 to 79, which exhibits an intra-subject coefficient of variation underfed conditions for the AUC_(0-t) of less than about 35%.

81. The oral pharmaceutical composition of any one of embodiments 75 to79, which exhibits an inter-subject coefficient of variation under fedconditions for the AUC_(0-t) of less than about 35%.

82. The oral pharmaceutical composition of any one of embodiments 75 to81, which exhibits a ratio in the range from about 0.70 to about 1.43for AUC_(0-t) between the oral pharmaceutical composition and areference composition with the 90% confidence interval.

83. The oral pharmaceutical composition of any one of embodiments 75 to81, which, upon administration under fed conditions, exhibits a relativebioavailability (F_(rel)) of greater than about 150% relative to areference composition under fed conditions.

84. The oral pharmaceutical composition of any one of embodiments 75 to83, which exhibits a minimum inhibitory concentration (MIC) value ofless than about 16 mcg/ml.

85. The oral pharmaceutical composition of embodiment 84, which exhibitsan AUC/MIC ratio of about 25 or greater.

86. An oral pharmaceutical composition comprising itraconazole, whereinthe composition exhibits an AUC_(0-t) which is 80% to 125% of about 7.0h*ng/ml to about 12.4 h*ng/ml per milligram of itraconazole followingadministration of the composition to a subject under fasting conditions.

87. The oral pharmaceutical composition of embodiment 86, wherein thecomposition exhibits a C_(max) which is 80% to 125% of about 1.2 ng/mlto about 1.5 ng/ml per milligram of itraconazole followingadministration of the composition to a subject under fasting conditions.

88. The oral pharmaceutical composition of embodiment 86 or 87, whereinthe composition exhibits reduced food effect as compared to a referencecomposition of itraconazole.

89. The oral pharmaceutical composition of any one of embodiments 86 to88, which under fasting conditions is therapeutically similar to areference composition under fed conditions.

90. The oral pharmaceutical composition of any one of embodiments 86 to89, wherein under fed conditions the composition is substantiallysimilar to the same composition under fasting conditions.

91. The oral pharmaceutical composition form of any one of embodiments86 to 90, which exhibits an intra-subject coefficient of variation underfed conditions for the AUC_(0-t) of less than about 35%.

92. The oral pharmaceutical composition of any one of embodiments 86 to90, which exhibits an inter-subject coefficient of variation under fedconditions for the AUC_(0-t) of less than about 35%.

93. The oral pharmaceutical composition of any one of embodiments 86 to92, which exhibits a ratio in the range from about 0.70 to about 1.43for AUC_(0-t) between the oral pharmaceutical composition and areference composition with the 90% confidence interval.

94. The oral pharmaceutical composition of any one of embodiments 86 to93, which, upon administration under fed conditions, exhibits a relativebioavailability (F_(rel)) of greater than about 150% relative to areference composition under fed conditions.

95. The oral pharmaceutical composition of any one of embodiments 86 to94, which exhibits a minimum inhibitory concentration (MIC) value ofless than about 16 mcg/ml.

96. The oral pharmaceutical composition of embodiment 95, which exhibitsan AUC/MIC ratio of about 25 or greater.

97. An oral pharmaceutical composition comprising itraconazole, whichexhibits an intra-subject coefficient of variation under fed conditionsfor the AUC_(0-t) of less than about 35%.

98. The oral pharmaceutical composition of embodiment 97, which exhibitsan intra-subject coefficient of variation under fed conditions for theAUC_(0-t) of less than about 35%.

99. The oral pharmaceutical composition of embodiments 97 or 98, whereinthe amount of itraconazole in the composition is about 50% to about 65%by weight of the amount of itraconazole in a reference composition.

100. An oral pharmaceutical composition comprising itraconazole, whichexhibits an inter-subject coefficient of variation under fed conditionsfor the AUC_(0-t) of less than about 35%.

101. The oral pharmaceutical composition of embodiments 100, whichexhibits an inter-subject coefficient of variation under fed conditionsfor the AUC_(0-t) of less than about 35%.

102. The oral pharmaceutical composition of embodiment 100 or 101,wherein the amount of itraconazole in the composition is about 50% toabout 65% by weight of the amount of itraconazole in a referencecomposition.

103. The oral pharmaceutical composition of embodiment 97 or 100,wherein the amount of itraconazole in the composition is about 50 mg.

104. The oral pharmaceutical composition of embodiment 97 or 100,wherein the amount of itraconazole in the composition is about 65 mg.

105. The oral pharmaceutical composition of any one of embodiments 97 to104, which exhibits a minimum inhibitory concentration (MIC) value ofless than about 16 mcg/ml.

106. The oral pharmaceutical composition of embodiment 105, whichexhibits an AUC/MIC ratio of about 25 or greater.

107. An oral pharmaceutical composition comprising itraconazole, whereinthe composition under fed conditions is substantially similar to thesame composition under fasting conditions.

108. The oral pharmaceutical composition of embodiment 107, wherein theamount of itraconazole in the composition is about 50% to about 65% byweight of the amount of itraconazole in a reference composition.

109. The oral pharmaceutical composition of embodiment 107 or 108, whichexhibits a difference of less than about 35% between a AUC_(0-t) underfasting conditions and a AUC_(0-t) under fed conditions.

110. The oral pharmaceutical composition of any one of embodiments 107to 109, which under fasting conditions is therapeutically similar to areference composition under fed conditions.

111. The oral pharmaceutical composition of any one of embodiments 107to 110, wherein the composition exhibits an AUC_(0-t) which is 80% to125% of about 8.8 h*ng/ml to about 14.8 h*ng/ml per milligram ofitraconazole following administration of the composition to a subjectunder fed conditions.

112. The oral pharmaceutical composition of any one of embodiments 107to 111, wherein the composition exhibits an AUC_(0-t) which is 80% to125% of about 7.0 h*ng/ml to about 12.4 h*ng/ml per milligram ofitraconazole following administration of the composition to a subjectunder fasting conditions.

113. The oral pharmaceutical composition of any one of embodiments 107to 112, wherein the amount of itraconazole in the composition is about50 mg.

114. The oral pharmaceutical composition of any one of embodiments 107to 112, wherein the amount of itraconazole in the composition is about65 mg.

115. The oral pharmaceutical composition of any one of embodiments 107to 114, which exhibits a minimum inhibitory concentration (MIC) value ofless than about 16 mcg/ml.

116. The oral pharmaceutical composition of embodiment 115, whichexhibits an AUC/MIC ratio of about 25 or greater.

117. A method of reducing food effect of itraconazole in a subjectcomprising administering to the subject an oral pharmaceuticalcomposition comprising about 50 mg of itraconazole, and the compositionprovides an AUC_(0-t) which is 80% to 125% of about 440 h*ng/ml to about740 h*ng/ml following administration of the composition to a subjectunder fed conditions.

118. The method of embodiment 117, wherein the composition exhibits anAUC_(0-t) which is 80% to 125% of about 350 h*ng/ml to about 620 h*ng/mlfollowing administration of the composition to a subject under fastingconditions.

119. A method of reducing food effect of itraconazole in a subjectcomprising administering to the subject an oral pharmaceuticalcomposition comprising about 65 mg of itraconazole, and the compositionprovides an AUC_(0-t) which is 80% to 125% of about 650 h*ng/ml to about1200 h*ng/ml following administration of the composition to a subjectunder fed conditions.

120. The method of embodiment 119, wherein the composition exhibits anAUC_(0-t) which is 80% to 125% of about 450 h*ng/ml to about 900 h*ng/mlfollowing administration of the composition to a subject under fastingconditions.

121. A method of reducing food effect of itraconazole in a subjectcomprising administering to the subject an oral pharmaceuticalcomposition comprising of itraconazole, and the composition provides anAUC_(0-t) which is 80% to 125% of about 8.8 h*ng/ml to about 14.8h*ng/ml per milligram of itraconazole following administration of thecomposition to a subject under fed conditions.

122. The method of embodiment 121, wherein the composition provides anAUC_(0-t) which is 80% to 125% of about 7.0 h*ng/ml to about 12.4h*ng/ml per milligram of itraconazole following administration of thecomposition to a subject under fasting conditions.

123. A method of reducing intra-subject variability of itraconazolecomprising administering to a subject an oral pharmaceutical compositioncomprising itraconazole, and the composition exhibits an intra-subjectcoefficient of variation under fed conditions for the AUC_(0-t) of lessthan about 35%.

124. A method of reducing inter-subject variability of itraconazolecomprising administering to subjects an oral pharmaceutical compositioncomprising itraconazole, and the composition exhibits an inter-subjectcoefficient of variation under fed conditions for the AUC_(0-t) of lessthan about 35%.

125. A method of treating onychomycosis comprising administering to asubject an oral pharmaceutical composition comprising itraconazole,wherein the amount of itraconazole in the composition is about 50% toabout 65% by weight of the amount of itraconazole in a referencecomposition and the composition is therapeutically equivalent to thereference composition.

126. A method of treating onychomycosis comprising administering to asubject an oral pharmaceutical composition comprising itraconazole,wherein the amount of itraconazole in the composition is about 50% toabout 65% by weight of the amount of itraconazole in a referencecomposition and the method provides an effective cure with faster onsetefficacy as compared to the reference composition.

127. The method of 126, wherein the method exhibits efficacy end pointsat a time when the reference composition does not exhibits efficacy endpoints.

128. The method of 127, wherein the efficacy end points is at week five,six, seven, eight, or nine.

129. A method of treating a disease or condition comprisingco-administering to a subject

-   -   an oral pharmaceutical composition comprising itraconazole; and    -   a gastric acid suppressor or neutralizer.

130. A method of treating cancer comprising administering to a subjectan oral pharmaceutical composition of any one of embodiments 1 to 100.

131. The method of 130, wherein the cancer is prostate cancer, skincancer, or lung cancer.

The detailed description herein describes various aspects andembodiments of the invention, however, unless otherwise specified, noneof those are intended to be limiting. Indeed, a person of skill in theart, having read this disclosure, will envision variations, alterations,and adjustments that can be made without departing from the scope andspirit of the invention, all of which should be considered to be part ofthe invention unless otherwise specified. Applicants thus envision thatthe invention described herein will be limited only by the appendedclaims.

The invention claimed is:
 1. An oral pharmaceutical compositioncomprising about 50 mg of itraconazole, wherein the composition exhibitsan AUCO-t which is 80% to 125% of about 650 h*ng/ml to about 1200h*ng/ml following administration of the composition to a subject underfed conditions.
 2. The oral pharmaceutical composition of claim 1,wherein the composition exhibits a Cmax which is 80% to 125% of about 65ng/ml to about 100 ng/ml following administration of the composition toa subject under fed conditions.
 3. The oral pharmaceutical compositionof claim 1, wherein the composition exhibits reduced food effect ascompared to a reference composition of itraconazole.
 4. The oralpharmaceutical composition of claim 1, which under fasting conditions istherapeutically similar to a reference composition under fed conditions.5. The oral pharmaceutical composition of claim 1, wherein thecomposition under fed conditions is substantially similar to the samecomposition under fasting conditions as to food effect.
 6. The oralpharmaceutical composition of claim 1, which exhibits reducedintra-subject variability as compared to a reference composition ofitraconazole.
 7. The oral pharmaceutical composition of claim 1, whichexhibits reduced inter-subject variability as compared to a referencecomposition of itraconazole.
 8. An oral pharmaceutical compositioncomprising about 65 mg of itraconazole, wherein the composition exhibitsan AUCO-t which is 80% to 125% of about 450 h*ng/ml to about 900 h*ng/mlfollowing administration of the composition to a subject under fastingconditions.
 9. The oral pharmaceutical composition of claim 8, whereinthe composition exhibits a Cmax which is 80% to 125% of about 36 ng/mlto about 70 ng/ml following administration of the composition to asubject under fasting conditions.
 10. The oral pharmaceuticalcomposition of claim 8, wherein the composition exhibits reduced foodeffect as compared to a reference composition of itraconazole.
 11. Theoral pharmaceutical composition of claim 8, which under fastingconditions is therapeutically similar to a reference composition underfed conditions.
 12. The oral pharmaceutical composition of claim 8,wherein the composition under fed conditions is substantially similar tothe same composition under fasting conditions as to food effect.
 13. Theoral pharmaceutical composition of claim 8, which exhibits a reducedintra-subject variability as compared to a reference composition ofitraconazole.
 14. The oral pharmaceutical composition of claim 8, whichexhibits a reduced inter-subject variability as compared to a referencecomposition of itraconazole.
 15. The oral pharmaceutical composition ofclaim 8, exhibits an AUCO-t which is 80% to 125% of about 650 h*ng/ml toabout 1200 h*ng/ml following administration of the composition to asubject under fed conditions.
 16. An oral pharmaceutical compositioncomprising itraconazole, wherein the composition exhibits an AUCO-twhich is 80% to 125% of about 10.0 h*ng/ml to about 18.0 h*ng/ml permilligram of itraconazole following administration of the composition toa subject under fed conditions.
 17. The oral pharmaceutical compositionof claim 16, wherein the composition exhibits a Cmax which is 80% to125% of about 1.31 ng/ml to about 1.54 ng/ml per milligram ofitraconazole following administration of the composition to a subjectunder fed conditions.
 18. The oral pharmaceutical composition of claim16, wherein the composition exhibits reduced food effect as compared toa reference composition of itraconazole.
 19. The oral pharmaceuticalcomposition of claim 16, which under fasting conditions istherapeutically similar to a reference composition under fed conditions.20. The oral pharmaceutical composition of claim 16, which exhibits anintra-subject coefficient of variation under fed conditions for theAUCO-t of about 35% or less.